АЛЛОСТЕРИЧЕСКИЕ САЙТЫ И АЛЛОСТЕРИЧЕСКИЕ РЕГУЛЯТОРЫ G-БЕЛОК-СОПРЯЖЕННЫХ РЕЦЕПТОРОВ – СЕРЫЕ КАРДИНАЛЫ СИГНАЛЬНОЙ ТРАНСДУКЦИИ
Том 59 № 7 (2023), Обзоры
Том 59 № 7 (2023)

АЛЛОСТЕРИЧЕСКИЕ САЙТЫ И АЛЛОСТЕРИЧЕСКИЕ РЕГУЛЯТОРЫ G-БЕЛОК-СОПРЯЖЕННЫХ РЕЦЕПТОРОВ – СЕРЫЕ КАРДИНАЛЫ СИГНАЛЬНОЙ ТРАНСДУКЦИИ

Обзоры
Опубликовано: December 9, 2023
Александр Олегович Шпаков
Институт эволюционной физиологии и биохимии им. И.М. Сеченова РАН, Санкт-Петербург
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Ключевые слова

аллостерический регулятор
G-белок-сопряженный рецептор
аллостерический сайт
ортостерический агонист
сигнальная трансдукция
гетеротримерный G-белок
β-аррестин
рецепторный комплекс

Аннотация

Мембранные рецепторы, сопряженные с G-белками (GPCR), являются ключевыми компонентами большинства эукариотических сигнальных систем, осуществляя передачу внешних сигналов к внутриклеточным эффекторным белкам. Активация GPCR осуществляется посредством специфического связывания различных по природе лигандов с их ортостерическим сайтом. Однако регуляция сродства ортостерического агониста к рецептору, контроль эффективности ответа, а также выбор предпочтительно активируемого внутриклеточного сигнального каскада осуществляются с помощью аллостерических механизмов. Это обусловлено присутствием в GPCR множества аллостерических сайтов, которые различаются по структурно-функциональной организации и топологии в молекуле рецептора, располагаясь во всех его функциональных субдоменах. Эндогенными регуляторами этих сайтов являются простые ионы (Na+, Zn2+, Mg2+, Ca2+, Cl- и другие), липиды (холестерин, фосфолипиды, стероиды), аминокислоты и их производные, полипептиды, а также сигнальные белки, образующие с GPCR функционально активные комплексы (G-белки, β-аррестины, RAMP), и аутоантитела к внеклеточным участкам GPCR. По фармакологической активности лиганды аллостерических сайтов GPCR подразделяют на позитивные, негативные или нейтральные модуляторы эффектов ортостерических агонистов, а также на полные и инверсионные агонисты или нейтральные антагонисты, которые влияют на базальную активность рецептора в отсутствие ортостерического агониста, хотя возможно совмещение свойств модулятора и агониста. Множественность аллостерических сайтов и аллостерических регуляторов, сложные взаимодействия между ними, вовлечение аллостерических механизмов в формирование рецепторных комплексов играют ключевую роль в тонкой настройке функциональной активности сигнальных каскадов, в предвзятом агонизме, предопределяют процессы десенситизации рецепторов и судьбу рецепторного комплекса после передачи гормонального сигнала. В обзоре суммированы и проанализированы современные представления и новые тенденции в области изучения аллостерической регуляции GPCR, локализации и функциональной роли аллостерических сайтов, их эндогенных и синтетических лигандах. В качестве примера подробно рассмотрены синтетические аллостерические регуляторы рецепторов тиреотропного и лютеинизирующего гормонов, как потенциальных лекарственных препаратов для коррекции эндокринных расстройств.

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Литература

Sriram K, Insel PA (2018) G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Mol Pharmacol 93:251–258. s://doi.org/10.1124/mol.117.111062

Yang D, Zhou Q, Labroska V, Qin S, Darbalaei S, Wu Y, Yuliantie E, Xie L, Tao H, Cheng J, Liu Q, Zhao S, Shui W, Jiang Y, Wang MW (2021) G protein-coupled receptors: structure- and function-based drug discovery. Signal Transduct Target Ther 6:7. https://doi.org/10.1038/s41392-020-00435-w

Mirzadegan T, Benkö G, Filipek S, Palczewski K (2003) Sequence analyses of G-protein-coupled receptors: similarities to rhodopsin. Biochemistry 42:2759–2767. s://doi.org/10.1021/bi027224+

Fredriksson R, Lagerström MC, Lundin LG, Schiöth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63:1256–1272. s://doi.org/10.1124/mol.63.6.1256

Schiöth HB, Fredriksson R (2005) The GRAFS classification system of G-protein coupled receptors in comparative perspective. Gen Comp Endocrinol 142:94–101. s://doi.org/10.1016/j.ygcen.2004.12.018

Erlandson SC, McMahon C, Kruse AC (2018) Structural Basis for G Protein-Coupled Receptor Signaling. Ann Rev Biophys 47:1–18. s://doi.org/10.1146/annurev-biophys-070317-032931

Congreve M, de Graaf C, Swain NA, Tate CG (2020) Impact of GPCR Structures on Drug Discovery. Cell 181:81–91. s://doi.org/10.1016/j.cell.2020.03.003

Pelé J, Abdi H, Moreau M, Thybert D, Chabbert M (2011) Multidimensional scaling reveals the main evolutionary pathways of class A G-protein-coupled receptors. PLoS One 6:e19094. s://doi.org/10.1371/journal.pone.0019094

Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739–745. s://doi.org/10.1126/science.289.5480.739

Schwartz TW, Frimurer TM, Holst B, Rosenkilde MM, Elling CE (2006) Molecular mechanism of 7TM receptor activation--a global toggle switch model. Ann Rev Pharmacol Toxicol 46:481–519. s://doi.org/10.1146/annurev.pharmtox.46.120604.141218

Kobilka BK (2007) G protein coupled receptor structure and activation. Biochim Biophys Acta 1768:794–807. s://doi.org/10.1016/j.bbamem.2006.10.021

Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318:1258–1265. https://doi.org/10.1126/science.1150577

Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK (2007) Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 450:383–387. s://doi.org/10.1038/nature06325

Liang YL, Khoshouei M, Radjainia M, Zhang Y, Glukhova A, Tarrasch J, Thal DM, Furness SGB, Christopoulos G, Coudrat T, Danev R, Baumeister W, Miller LJ, Christopoulos A, Kobilka BK, Wootten D, Skiniotis G, Sexton PM (2017) Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature 2017 546:118–123. s://doi.org/10.1038/nature22327

Yang S, Wu Y, Xu TH, de Waal PW, He Y, Pu M, Chen Y, DeBruine ZJ, Zhang B, Zaidi SA, Popov P, Guo Y, Han GW, Lu Y, Suino-Powell K, Dong S, Harikumar KG, Miller LJ, Katritch V, Xu HE, Shui W, Stevens RC, Melcher K, Zhao S, Xu F (2018) Crystal structure of the Frizzled 4 receptor in a ligand-free state. Nature 560:666–670. s://doi.org/10.1038/s41586-018-0447-x

Liessmann F, Künze G, Meiler J (2023) Improving the Modeling of Extracellular Ligand Binding Pockets in RosettaGPCR for Conformational Selection. Int J Mol Sci 24:7788. s://doi.org/10.3390/ijms24097788

An K, Zhu X, Bai C (2022) The Nature of Functional Features of Different Classes of G-Protein-Coupled Receptors. Biology (Basel) 11:1839. s://doi.org/10.3390/biology11121839

Noonan T, Denzinger K, Talagayev V, Chen Y, Puls K, Wolf CA, Liu S, Nguyen TN, Wolber G (2022) Mind the Gap-Deciphering GPCR Pharmacology Using 3D Pharmacophores and Artificial Intelligence. Pharmaceuticals (Basel) 15:1304. s://doi.org/10.3390/ph15111304

Wettschureck N, Offermanns S (2005) Mammalian G proteins and their cell type specific functions. Physiol Rev 85:1159–1204. s://doi.org/10.1152/physrev.00003.2005

McCudden CR, Hains MD, Kimple RJ, Siderovski DP, Willard FS (2005) G-protein signaling: back to the future. Cell Mol Life Sci 62:551–577. s://doi.org/10.1007/s00018-004-4462-3

Dohlman HG, Jones JC (2012) Signal activation and inactivation by the Gα helical domain: a long-neglected partner in G protein signaling. Sci Signal 5:re2. s://doi.org/10.1126/scisignal.2003013

Schappi JM, Krbanjevic A, Rasenick MM (2014) Tubulin, actin and heterotrimeric G proteins: coordination of signaling and structure. Biochim Biophys Acta 1838:674–681. s://doi.org/10.1016/j.bbamem.2013.08.026

Shpakov AO (2003) Participation of charged amino acid residues of cytoplasmic loops of serpentine type receptors in the process of transmission of hormonal signal. J Evol Biochem Physiol 39:266–280. s://doi.org/10.1023/A:1026135522916

Probst WC, Snyder LA, Schuster DI, Brosius J, Sealfon SC (1992) Sequence alignment of the G-protein coupled receptor superfamily. DNA Cell Biol 11:1–20. s://doi.org/10.1089/dna.1992.11.1

Gether U (2000) Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr Rev 21:90–113. s://doi.org/10.1210/edrv.21.1.0390

LeBlanc MG, Lehmann R (2017) Domain-specific control of germ cell polarity and migration by multifunction Tre1 GPCR. J Cell Biol 216:2945–2958. s://doi.org/10.1083/jcb.201612053

Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S (2012) Action of molecular switches in GPCRs--theoretical and experimental studies. Curr Med Chem 19:1090–10109. s://doi.org/10.2174/092986712799320556

Venkatakrishnan AJ, Deupi X, Lebon G, Heydenreich FM, Flock T, Miljus T, Balaji S, Bouvier M, Veprintsev DB, Tate CG, Schertler GF, Babu MM (2016) Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region. Nature 536:484–487. s://doi.org/10.1038/nature19107

Mitchell R, McCulloch D, Lutz E, Johnson M, MacKenzie C, Fennell M, Fink G, Zhou W, Sealfon SC (1998) Rhodopsin-family receptors associate with small G proteins to activate phospholipase D. Nature 392:411–414. s://doi.org/10.1038/32937

Brzostowski JA, Kimmel AR (2001) Signaling at zero G: G-protein-independent functions for 7-TM receptors. Trends Biochem Sci 26:291–297. s://doi.org/10.1016/s0968-0004(01)01804-7

Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308:512–517. s://doi.org/10.1126/science.1109237

Rajagopal S, Rajagopal K, Lefkowitz RJ (2010) Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 9:373–386. s://doi.org/10.1038/nrd3024

Magalhaes AC, Dunn H, Ferguson SS (2012) Regulation of GPCR activity, trafficking and localization by GPCR-interacting proteins. Br J Pharmacol 165:1717–1736. s://doi.org/10.1111/j.1476-5381.2011.01552.x

Aydin Y, Coin I (2021) Biochemical insights into structure and function of arrestins. FEBS J 288:2529–2549. s://doi.org/10.1111/febs.15811

Kim K, Han Y, Duan L, Chung KY (2022) Scaffolding of Mitogen-Activated Protein Kinase Signaling by β-Arrestins. Int J Mol Sci 23:1000. s://doi.org/10.3390/ijms23021000

Smith JS, Pack TF (2021) Noncanonical interactions of G proteins and β-arrestins: from competitors to companions. FEBS J 288:2550–2561. s://doi.org/10.1111/febs.15749

Alvarez CE (2008) On the origins of arrestin and rhodopsin. BMC Evol Biol 8:222. s://doi.org/10.1186/1471-2148-8-222

Peterson YK, Luttrell LM (2017) The Diverse Roles of Arrestin Scaffolds in G Protein-Coupled Receptor Signaling. Pharmacol Rev 69:256–297. s://doi.org/10.1124/pr.116.013367

Dores MR, Trejo J (2015) GPCR sorting at multivesicular endosomes. Methods Cell Biol 130:319–332. s://doi.org/10.1016/bs.mcb.2015.05.006

Li X, Rosciglione S, Laniel A, Lavoie C (2019) Combining RNAi and Immunofluorescence Approaches to Investigate Post-endocytic Sorting of GPCRs into Multivesicular Bodies. Methods Mol Biol 1947:303–322. s://doi.org/10.1007/978-1-4939-9121-1_17

Daaka Y, Luttrell LM, Ahn S, Della Rocca GJ, Ferguson SS, Caron MG, Lefkowitz RJ (1998) Essential role for G protein-coupled receptor endocytosis in the activation of mitogen-activated protein kinase. J Biol Chem 273:685–688. s://doi.org/10.1074/jbc.273.2.685

Ma L, Pei G (2007) Beta-arrestin signaling and regulation of transcription. J Cell Sci 120:213–228. s://doi.org/10.1242/jcs.03338

Tian X, Kang DS, Benovic JL (2014) β-arrestins and G protein-coupled receptor trafficking. Handb Exp Pharmacol 219:173–186. s://doi.org/10.1007/978-3-642-41199-1_9

Seyedabadi M, Ghahremani MH, Albert PR (2019) Biased signaling of G protein coupled receptors (GPCRs): Molecular determinants of GPCR/transducer selectivity and therapeutic potential. Pharmacol Ther 200:148–178. s://doi.org/10.1016/j.pharmthera.2019.05.006

Seyedabadi M, Gharghabi M, Gurevich EV, Gurevich VV (2022) Structural basis of GPCR coupling to distinct signal transducers: implications for biased signaling. Trends Biochem Sci 47:570–581. s://doi.org/10.1016/j.tibs.2022.03.009

Apostolakou AE, Baltoumas FA, Stravopodis DJ, Iconomidou VA (2020) Extended Human G-Protein Coupled Receptor Network: Cell-Type-Specific Analysis of G-Protein Coupled Receptor Signaling Pathways. J Proteome Res 19:511–524. s://doi.org/10.1021/acs.jproteome.9b00754

Ma TL, Zhou Y, Zhang CY, Gao ZA, Duan JX (2021) The role and mechanism of β-arrestin2 in signal transduction. Life Sci 275:119364. s://doi.org/10.1016/j.lfs.2021.119364

Chen Q, Tesmer JJG (2022) G protein-coupled receptor interactions with arrestins and GPCR kinases: The unresolved issue of signal bias. J Biol Chem 298(9):102279. s://doi.org/10.1016/j.jbc.2022.102279

Jiang H, Galtes D, Wang J, Rockman HA (2022) G protein-coupled receptor signaling: transducers and effectors. Am J Physiol Cell Physiol 323:C731–C748. s://doi.org/10.1152/ajpcell.00210.2022

DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK (2007) Beta-arrestins and cell signaling. Annu Rev Physiol 69:483–510. s://doi.org/10.1146/annurev.physiol.69.022405.154749

Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin F, Kawakatsu H, Owada K, Luttrell DK, Caron MG, Lefkowitz RJ (1999) Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science 283:655–661. s://doi.org/10.1126/science.283.5402.655

Barlic J, Andrews JD, Kelvin AA, Bosinger SE, DeVries ME, Xu L, Dobransky T, Feldman RD, Ferguson SS, Kelvin DJ (2000) Regulation of tyrosine kinase activation and granule release through beta-arrestin by CXCRI. Nat Immunol 1:227–233. s://doi.org/10.1038/79767

Mazzi P, Caveggion E, Lapinet-Vera JA, Lowell CA, Berton G (2015) The Src-Family Kinases Hck and Fgr Regulate Early Lipopolysaccharide-Induced Myeloid Cell Recruitment into the Lung and Their Ability To Secrete Chemokines. J Immunol 195:2383–2395. s://doi.org/10.4049/jimmunol.1402011

Perez I, Berndt S, Agarwal R, Castro MA, Vishnivetskiy SA, Smith JC, Sanders CR, Gurevich VV, Iverson TM (2022) A Model for the Signal Initiation Complex Between Arrestin-3 and the Src Family Kinase Fgr. J Mol Biol 434:167400. s://doi.org/10.1016/j.jmb.2021.167400

Kim IM, Wang Y, Park KM, Tang Y, Teoh JP, Vinson J, Traynham CJ, Pironti G, Mao L, Su H, Johnson JA, Koch WJ, Rockman HA (2014) β-arrestin1-biased β1-adrenergic receptor signaling regulates microRNA processing. Circ Res 114:833–844. https://doi.org/10.1161/CIRCRESAHA.114.302766

Teoh JP, Bayoumi AS, Aonuma T, Xu Y, Johnson JA, Su H, Weintraub NL, Tang Y, Kim IM (2018) β-arrestin-biased agonism of β-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling. J Mol Cell Cardiol 118:225–236. s://doi.org/10.1016/j.yjmcc.2018.04.001

Wang J, Pani B, Gokhan I, Xiong X, Kahsai AW, Jiang H, Ahn S, Lefkowitz RJ, Rockman HA (2021) β-Arrestin-Biased Allosteric Modulator Potentiates Carvedilol-Stimulated β Adrenergic Receptor Cardioprotection. Mol Pharmacol 100:568–579. s://doi.org/10.1124/molpharm.121.000359

Saulière A, Bellot M, Paris H, Denis C, Finana F, Hansen JT, Altié MF, Seguelas MH, Pathak A, Hansen JL, Sénard JM, Galés C (2012) Deciphering biased-agonism complexity reveals a new active AT1 receptor entity. Nat Chem Biol 8:622–630. s://doi.org/10.1038/nchembio.961

Strachan RT, Sun JP, Rominger DH, Violin JD, Ahn S, Rojas Bie Thomsen A, Zhu X, Kleist A, Costa T, Lefkowitz RJ (2014) Divergent transducer-specific molecular efficacies generate biased agonism at a G protein-coupled receptor (GPCR). J Biol Chem 289:14211–14224. s://doi.org/10.1074/jbc.M114.548131

O'Hayre M, Eichel K, Avino S, Zhao X, Steffen DJ, Feng X, Kawakami K, Aoki J, Messer K, Sunahara R, Inoue A, von Zastrow M, Gutkind JS (2017) Genetic evidence that β-arrestins are dispensable for the initiation of β2-adrenergic receptor signaling to ERK. Sci Signal 10:eaal3395. s://doi.org/10.1126/scisignal.aal3395

Grundmann M, Merten N, Malfacini D, Inoue A, Preis P, Simon K, Rüttiger N, Ziegler N, Benkel T, Schmitt NK, Ishida S, Müller I, Reher R, Kawakami K, Inoue A, Rick U, Kühl T, Imhof D, Aoki J, König GM, Hoffmann C, Gomeza J, Wess J, Kostenis E (2018) Lack of beta-arrestin signaling in the absence of active G proteins. Nat Commun 9:341. https://doi.org/10.1038/s41467-017-02661-3

Haider RS, Matthees ESF, Drube J, Reichel M, Zabel U, Inoue A, Chevigné A, Krasel C, Deupi X, Hoffmann C (2022) β-arrestin1 and 2 exhibit distinct phosphorylation-dependent conformations when coupling to the same GPCR in living cells. Nat Commun 13:5638. s://doi.org/10.1038/s41467-022-33307-8

Oesterhelt D (1998) The structure and mechanism of the family of retinal proteins from halophilic archaea. Curr Opin Struct Biol 8:489–500. s://doi.org/10.1016/s0959-440x(98)80128-0

Fuhrman JA, Schwalbach MS, Stingl U (2008) Proteorhodopsins: an array of physiological roles? Nat Rev Microbiol 6:488–494. s://doi.org/10.1038/nrmicro1893

Ernst OP, Lodowski DT, Elstner M, Hegemann P, Brown LS, Kandori H (2014) Microbial and animal rhodopsins: structures, functions, and molecular mechanisms. Chem Rev 114:126–163. s://doi.org/10.1021/cr4003769

Mackin KA, Roy RA, Theobald DL (2014) An empirical test of convergent evolution in rhodopsins. Mol Biol Evol 31:85–95. s://doi.org/10.1093/molbev/mst171

Zhang Z, Jin Z, Zhao Y, Zhang Z, Li R, Xiao J, Wu J (2014) Systematic study on G-protein couple receptor prototypes: did they really evolve from prokaryotic genes? IET Syst Biol 2014 8:154–161. s://doi.org/10.1049/iet-syb.2013.0037

O'Hara PJ, Sheppard PO, Thøgersen H, Venezia D, Haldeman BA, McGrane V, Houamed KM, Thomsen C, Gilbert TL, Mulvihill ER (1993) The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins. Neuron 11:41–52. s://doi.org/10.1016/0896-6273(93)90269-w

Taylor EW, Agarwal A (1993) Sequence homology between bacteriorhodopsin and G-protein coupled receptors: exon shuffling or evolution by duplication? FEBS Lett 325:161–166. s://doi.org/10.1016/0014-5793(93)81065-8

Soppa J (1994) Two hypotheses--one answer. Sequence comparison does not support an evolutionary link between halobacterial retinal proteins including bacteriorhodopsin and eukaryotic G-protein-coupled receptors. FEBS Lett 342:7–11. s://doi.org/10.1016/0014-5793(94)80573-3

Larusso ND, Ruttenberg BE, Singh AK, Oakley TH (2008) Type II opsins: evolutionary origin by internal domain duplication? J Mol Evol 66:417–423. s://doi.org/10.1007/s00239-008-9076-6

Kojima K, Sudo Y (2023) Convergent evolution of animal and microbial rhodopsins. RSC Adv 13:5367–5381. s://doi.org/10.1039/d2ra07073a

Zhai Y, Heijne WH, Smith DW, Saier MH Jr (2001) Homologues of archaeal rhodopsins in plants, animals and fungi: structural and functional predications for a putative fungal chaperone protein. Biochim Biophys Acta 1511:206–223. s://doi.org/10.1016/s0005-2736(00)00389-8

Feuda R, Hamilton SC, McInerney JO, Pisani D (2012) Metazoan opsin evolution reveals a simple route to animal vision. Proc Natl Acad Sci U S A 109:18868–18872. s://doi.org/10.1073/pnas.1204609109

Krishnan A, Almén MS, Fredriksson R, Schiöth HB (2012) The origin of GPCRs: identification of mammalian like Rhodopsin, Adhesion, Glutamate and Frizzled GPCRs in fungi. PLoS One 7:e29817. s://doi.org/10.1371/journal.pone.0029817

Shpakov AO, Pertseva MN (2008) Signaling systems of lower eukaryotes and their evolution. Int Rev Cell Mol Biol 269:151–282. s://doi.org/10.1016/S1937-6448(08)01004-6

Xue C, Hsueh YP, Heitman J (2008) Magnificent seven: roles of G protein-coupled receptors in extracellular sensing in fungi. FEMS Microbiol Rev 32:1010–1032. s://doi.org/10.1111/j.1574-6976.2008.00131.x

Brown NA, Schrevens S, van Dijck P, Goldman GH (2018) Fungal G-protein-coupled receptors: mediators of pathogenesis and targets for disease control. Nat Microbiol 3:402–414. s://doi.org/10.1038/s41564-018-0127-5

Li L, Wright SJ, Krystofova S, Park G, Borkovich KA (2007) Heterotrimeric G protein signaling in filamentous fungi. Annu Rev Microbiol 61:423–452. s://doi.org/10.1146/annurev.micro.61.080706.093432

Overton MC, Chinault SL, Blumer KJ (2005) Oligomerization of G-protein-coupled receptors: lessons from the yeast Saccharomyces cerevisiae. Eukaryot Cell 4:1963–1970. https://doi.org/10.1128/EC.4.12.1963-1970.2005

Borkovich KA, Alex LA, Yarden O, Freitag M, Turner GE, Read ND, Seiler S, Bell-Pedersen D, Paietta J, Plesofsky N, Plamann M, Goodrich-Tanrikulu M, Schulte U, Mannhaupt G, Nargang FE, Radford A, Selitrennikoff C, Galagan JE, Dunlap JC, Loros JJ, Catcheside D, Inoue H, Aramayo R, Polymenis M, Selker EU, Sachs MS, Marzluf GA, Paulsen I, Davis R, Ebbole DJ, Zelter A, Kalkman ER, O'Rourke R, Bowring F, Yeadon J, Ishii C, Suzuki K, Sakai W, Pratt R (2004) Lessons from the genome sequence of Neurospora crassa: tracing the path from genomic blueprint to multicellular organism. Microbiol Mol Biol Rev 68:1–108. s://doi.org/10.1128/MMBR.68.1.1-108.2004

Lafon A, Han KH, Seo JA, Yu JH, d'Enfert C (2006) G-protein and cAMP-mediated signaling in aspergilli: a genomic perspective. Fungal Genet Biol 43:490–502. https://doi.org/10.1016/j.fgb.2006.02.001

Prabhu Y, Mondal S, Eichinger L, Noegel AA (2007) A GPCR involved in post aggregation events in Dictyostelium discoideum. Dev Biol 312:29–43. https://doi.org/10.1016/j.ydbio.2007.08.055

Dilks T, Halsey K, De Vos RP, Hammond-Kosack KE, Brown NA (2019) Non-canonical fungal G-protein coupled receptors promote Fusarium head blight on wheat. PLoS Pathog 15:e1007666. s://doi.org/10.1371/journal.ppat.1007666

Kou Y, Tan YH, Ramanujam R, Naqvi NI (2016) Structure-function analyses of the Pth11 receptor reveal an important role for CFEM motif and redox regulation in rice blast. New Phytol 214:330–342. s://doi.org/10.1111/nph.14347

van den Hoogen J, Govers F (2018) GPCR-bigrams: Enigmatic signaling components in oomycetes. PLoS Pathog 14:e1007064. s://doi.org/10.1371/journal.ppat.1007064

van den Hoogen DJ, Meijer HJG, Seidl MF, Govers F (2018) The Ancient Link between G-Protein-Coupled Receptors and C-Terminal Phospholipid Kinase Domains. mBio. 9:e02119-17. s://doi.org/10.1128/mBio.02119-17

Riyahi TY, Frese F, Steinert M, Omosigho NN, Glöckner G, Eichinger L, Orabi B, Williams RS, Noegel AA (2011) RpkA, a highly conserved GPCR with a lipid kinase domain, has a role in phagocytosis and anti-bacterial defense. PLoS One 6:e27311. s://doi.org/10.1371/journal.pone.0027311

Hua C, Meijer HJ, de Keijzer J, Zhao W, Wang Y, Govers F (2013) GK4, a G-protein-coupled receptor with a phosphatidylinositol phosphate kinase domain in Phytophthora infestans, is involved in sporangia development and virulence. Mol Microbiol 88:352–370. s://doi.org/10.1111/mmi.12190

Yang X, Zhao W, Hua C, Zheng X, Jing M, Li D, Govers F, Meijer HJ, Wang Y (2013) Chemotaxis and oospore formation in Phytophthora sojae are controlled by G-protein-coupled receptors with a phosphatidylinositol phosphate kinase domain. Mol Microbiol 88:382–394. s://doi.org/10.1111/mmi.12191

Шпаков АО (2009) Пептидные аутоиндукторы бактерий. Микробиология 78:291-303. [Shpakov AO (2009) [Bacterial autoinducing peptides]. Mikrobiologiia 78:291–303. (In Russ)].

Шпаков АО (2009) Сигнальные молекулы бактерий непептидной природы QS-типа. Микробиология 78:163–175. [Shpakov AO (2009) [Bacterial nonpeptide quorum-sensing signal molecules]. Mikrobiologiia 78:163–175. (In Russ).]

Liu Y, Wang X, Dong D, Guo L, Dong X, Leng J, Zhao B, Guo YD, Zhang N (2021) Research Advances in Heterotrimeric G-Protein α Subunits and Uncanonical G-Protein Coupled Receptors in Plants. Int J Mol Sci 22:8678. s://doi.org/10.3390/ijms22168678

Pandey S, Assmann SM (2004) The Arabidopsis putative G protein-coupled receptor GCR1 interacts with the G protein alpha subunit GPA1 and regulates abscisic acid signaling. Plant Cell 16:1616–1632. s://doi.org/10.1105/tpc.020321

Liu X, Yue Y, Li B, Nie Y, Li W, Wu WH, Ma L (2007) A G protein-coupled receptor is a plasma membrane receptor for the plant hormone abscisic acid. Science 315:1712–1716. s://doi.org/10.1126/science.1135882

Wei J, Li DX, Zhang JR, Shan C, Rengel Z, Song ZB, Chen Q (2018) Phytomelatonin receptor PMTR1-mediated signaling regulates stomatal closure in Arabidopsis thaliana. J Pineal Res 65:e12500. s://doi.org/10.1111/jpi.12500

Chakraborty N, Kanyuka K, Jaiswal DK, Kumar A, Arora V, Malik A, Gupta N, Hooley R, Raghuram N (2019) GCR1 and GPA1 coupling regulates nitrate, cell wall, immunity and light responses in Arabidopsis. Sci Rep 9:5838. s://doi.org/10.1038/s41598-019-42084-2

Chen JG, Pandey S, Huang J, Alonso JM, Ecker JR, Assmann SM, Jones AM (2004) GCR1 can act independently of heterotrimeric G-protein in response to brassinosteroids and gibberellins in Arabidopsis seed germination. Plant Physiol 135:907–915. s://doi.org/10.1104/pp.104.038992

Ma Y, Dai X, Xu Y, Luo W, Zheng X, Zeng D, Pan Y, Lin X, Liu H, Zhang D, Xiao J, Guo X, Xu S, Niu Y, Jin J, Zhang H, Xu X, Li L, Wang W, Qian Q, Ge S, Chong K (2015) COLD1 confers chilling tolerance in rice. Cell 160:1209–1221. s://doi.org/10.1016/j.cell.2015.01.046

Reboul J, Ewbank JJ (2016) GPCRs in invertebrate innate immunity. Biochem Pharmacol 114:82–87. s://doi.org/10.1016/j.bcp.2016.05.015

Gupta A, Singh V (2017) GPCR Signaling in C. elegans and Its Implications in Immune Response. Adv Immunol 136:203–226. s://doi.org/10.1016/bs.ai.2017.05.002

Liu N, Wang Y, Li T, Feng X (2021) G-Protein Coupled Receptors (GPCRs): Signaling Pathways, Characterization, and Functions in Insect Physiology and Toxicology. Int J Mol Sci 22:5260. s://doi.org/10.3390/ijms22105260

Guo S, Zhao T, Yun Y, Xie X (2022) Recent progress in assays for GPCR drug discovery. Am J Physiol Cell Physiol 323:C583–C594. s://doi.org/10.1152/ajpcell.00464.2021

Anctil M, Hayward DC, Miller DJ, Ball EE (2007) Sequence and expression of four coral G protein-coupled receptors distinct from all classifiable members of the rhodopsin family. Gene 392:14–21. s://doi.org/10.1016/j.gene.2006.10.025

Carre-Pierrat M, Baillie D, Johnsen R, Hyde R, Hart A, Granger L, Ségalat L (2006) Characterization of the Caenorhabditis elegans G protein-coupled serotonin receptors. Invert Neurosci 6:189–205. s://doi.org/10.1007/s10158-006-0033-z

Fernandez RW, Wei K, Wang EY, Mikalauskaite D, Olson A, Pepper J, Christie N, Kim S, Weissenborn S, Sarov M, Koelle MR (2020) Cellular Expression and Functional Roles of All 26 Neurotransmitter GPCRs in the C. elegans Egg-Laying Circuit. J Neurosci 40:7475–7488. s://doi.org/10.1523/JNEUROSCI.1357-20.2020

Phan P, Liang D, Zhao M, Wyeth RC, Fogarty C, Duke MG, McManus DP, Wang T, Cummins SF (2022) Analysis of rhodopsin G protein-coupled receptor orthologs reveals semiochemical peptides for parasite (Schistosoma mansoni) and host (Biomphalaria glabrata) interplay. Sci Rep 12:8243. s://doi.org/10.1038/s41598-022-11996-x

Olson AC, Butt AM, Christie NTM, Shelar A, Koelle MR (2023) Multiple Subthreshold GPCR Signals Combined by the G-Proteins Gαq and Gαs Activate the Caenorhabditis elegans Egg-Laying Muscles. J Neurosci 43:3789–3806. s://doi.org/10.1523/JNEUROSCI.2301-22.2023

Stafflinger E, Hansen KK, Hauser F, Schneider M, Cazzamali G, Williamson M, Grimmelikhuijzen CJ (2008) Cloning and identification of an oxytocin/vasopressin-like receptor and its ligand from insects. Proc Natl Acad Sci U S A 105:3262–3267. s://doi.org/10.1073/pnas.0710897105

Muratspahić E, Monjon E, Duerrauer L, Rogers SM, Cullen DA, Vanden Broeck J, Gruber CW (2020) Oxytocin/vasopressin-like neuropeptide signaling in insects. Vitam Horm 113:29–53. s://doi.org/10.1016/bs.vh.2019.08.011

Tu S, Xu R, Wang M, Xie X, Bao C, Zhu D (2021) Identification and characterization of expression profiles of neuropeptides and their GPCRs in the swimming crab, Portunus trituberculatus. PeerJ 9:e12179. s://doi.org/10.7717/peerj.12179

Ritschard EA, Fitak RR, Simakov O, Johnsen S (2019) Genomic signatures of G-protein-coupled receptor expansions reveal functional transitions in the evolution of cephalopod signal transduction. Proc Biol Sci 286:20182929. s://doi.org/10.1098/rspb.2018.2929

Fu H, Tian J, Shi C, Li Q, Liu S (2022) Ecological significance of G protein-coupled receptors in the Pacific oyster (Crassostrea gigas): Pervasive gene duplication and distinct transcriptional response to marine environmental stresses. Mar Pollut Bull 185:114269. s://doi.org/10.1016/j.marpolbul.2022.114269

Hauser F, Koch TL, Grimmelikhuijzen CJP (2022) Review: The evolution of peptidergic signaling in Cnidaria and Placozoa, including a comparison with Bilateria. Front Endocrinol (Lausanne) 13:973862. s://doi.org/10.3389/fendo.2022.973862

Bock A, Bermudez M (2021) Allosteric coupling and biased agonism in G protein-coupled receptors. FEBS J 288:2513–2528. s://doi.org/10.1111/febs.15783

Shpakov AO (2023) Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands. Int J Mol Sci 24:6187. s://doi.org/10.3390/ijms24076187

Grundmann M, Bender E, Schamberger J, Eitner F (2021) Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators. Int J Mol Sci 22:1763. s://doi.org/10.3390/ijms22041763

Kenakin T, Strachan RT (2018) PAM-Antagonists: A Better Way to Block Pathological Receptor Signaling? Trends Pharmacol Sci 39:748–765. s://doi.org/10.1016/j.tips.2018.05.001

Christopoulos A, Kenakin T (2002) G protein-coupled receptor allosterism and complexing. Pharmacol Rev 54:323–374. s://doi.org/10.1124/pr.54.2.323

Reinecke BA, Wang H, Zhang Y (2019) Recent Advances in the Drug Discovery and Development of Dualsteric/ Bitopic Activators of G Protein-Coupled Receptors. Curr Top Med Chem 19:2378–2392. s://doi.org/10.2174/1568026619666191009164609

Jakubík J, Randáková A, Chetverikov N, El-Fakahany EE, Doležal V (2020) The operational model of allosteric modulation of pharmacological agonism. Sci Rep 10:14421. https://doi.org/10.1038/s41598-020-71228-y

Kamal M, Jockers R (2009) Bitopic ligands: all-in-one orthosteric and allosteric. F1000 Biol Rep 1:77. s://doi.org/10.3410/B1-77

Valant C, Sexton PM, Christopoulos A (2009) Orthosteric/allosteric bitopic ligands: going hybrid at GPCRs. Mol Interv 9:125–135. s://doi.org/10.1124/mi.9.3.6

Valant C, Robert Lane J, Sexton PM, Christopoulos A (2012) The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. Annu Rev Pharmacol Toxicol 52:153–178. s://doi.org/10.1146/annurev-pharmtox-010611-134514

Lane JR, Sexton PM, Christopoulos A (2013) Bridging the gap: bitopic ligands of G-protein-coupled receptors. Trends Pharmacol Sci 34:59–66. s://doi.org/10.1016/j.tips.2012.10.003

Fronik P, Gaiser BI, Sejer Pedersen D (2017) Bitopic Ligands and Metastable Binding Sites: Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry. J Med Chem 60:4126–4134. s://doi.org/10.1021/acs.jmedchem.6b01601

Egyed A, Kiss DJ, Keserű GM (2022) The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs. Front Pharmacol 13:847788. s://doi.org/10.3389/fphar.2022.847788

Ferrisi R, Gado F, Polini B, Ricardi C, Mohamed KA, Stevenson LA, Ortore G, Rapposelli S, Saccomanni G, Pertwee RG, Laprairie RB, Manera C, Chiellini G (2022) Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CB2R). Front Chem 10:984069. s://doi.org/10.3389/fchem.2022.984069

Newman AH, Battiti FO, Bonifazi A (2020) 2016 Philip S. Portoghese Medicinal Chemistry Lectureship: Designing Bivalent or Bitopic Molecules for G-Protein Coupled Receptors. The Whole Is Greater Than the Sum of Its Parts. J Med Chem 63:1779–1797. https://doi.org/10.1021/acs.jmedchem.9b01105

Schrage R, Kostenis E (2017) Functional selectivity and dualsteric/bitopic GPCR targeting. Curr Opin Pharmacol 32:85–90. s://doi.org/10.1016/j.coph.2016.12.001

Steinfeld T, Mammen M, Smith JA, Wilson RD, Jasper JR (2007) A novel multivalent ligand that bridges the allosteric and orthosteric binding sites of the M2 muscarinic receptor. Mol Pharmacol 72:291–302. s://doi.org/10.1124/mol.106.033746

Antony J, Kellershohn K, Mohr-Andrä M, Kebig A, Prilla S, Muth M, Heller E, Disingrini T, Dallanoce C, Bertoni S, Schrobang J, Tränkle C, Kostenis E, Christopoulos A, Höltje HD, Barocelli E, De Amici M, Holzgrabe U, Mohr K (2009) Dualsteric GPCR targeting: a novel route to binding and signaling pathway selectivity. FASEB J 23:442–450. s://doi.org/10.1096/fj.08-114751

Jakubík J, El-Fakahany EE (2021) Allosteric Modulation of GPCRs of Class A by Cholesterol. Int J Mol Sci 22:1953. s://doi.org/10.3390/ijms22041953

Liu L, Fan Z, Rovira X, Xue L, Roux S, Brabet I, Xin M, Pin JP, Rondard P, Liu J (2021) Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface. Elife 10:e70188. s://doi.org/10.7554/eLife.70188

Hedderich JB, Persechino M, Becker K, Heydenreich FM, Gutermuth T, Bouvier M, Bünemann M, Kolb P (2022) The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites. Nat Commun 13:2567. s://doi.org/10.1038/s41467-022-29609-6

Persechino M, Hedderich JB, Kolb P, Hilger D (2022) Allosteric modulation of GPCRs: From structural insights to in silico drug discovery. Pharmacol Ther 237:108242. https://doi.org/10.1016/j.pharmthera.2022.108242

Vuckovic Z, Gentry PR, Berizzi AE, Hirata K, Varghese S, Thompson G, van der Westhuizen ET, Burger WAC, Rahmani R, Valant C, Langmead CJ, Lindsley CW, Baell JB, Tobin AB, Sexton PM, Christopoulos A, Thal DM (2019) Crystal structure of the M5 muscarinic acetylcholine receptor. Proc Natl Acad Sci U S A 116:26001–26007. s://doi.org/10.1073/pnas.1914446116

Felder CC, Goldsmith PJ, Jackson K, Sanger HE, Evans DA, Mogg AJ, Broad LM (2018) Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases. Neuropharmacology 136:449–458. s://doi.org/10.1016/j.neuropharm.2018.01.028

Christopoulos A (2014) Advances in G protein-coupled receptor allostery: from function to structure. Mol Pharmacol 86:463–478. s://doi.org/10.1124/mol.114.094342

Congreve M, Oswald C, Marshall FH (2017) Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs. Trends Pharmacol Sci 38:837–847. s://doi.org/10.1016/j.tips.2017.05.010

Lu S, Shen Q, Zhang J (2019) Allosteric Methods and Their Applications: Facilitating the Discovery of Allosteric Drugs and the Investigation of Allosteric Mechanisms. Acc Chem Res 52:492–500. s://doi.org/10.1021/acs.accounts.8b00570

Thal DM, Glukhova A, Sexton PM, Christopoulos A (2018) Structural insights into G-protein-coupled receptor allostery. Nature 559:45–53. s://doi.org/10.1038/s41586-018-0259-z

Ahn S, Kahsai AW, Pani B, Wang QT, Zhao S, Wall AL, Strachan RT, Staus DP, Wingler LM, Sun LD, Sinnaeve J, Choi M, Cho T, Xu TT, Hansen GM, Burnett MB, Lamerdin JE, Bassoni DL, Gavino BJ, Husemoen G, Olsen EK, Franch T, Costanzi S, Chen X, Lefkowitz RJ (2017) Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library. Proc Natl Acad Sci U S A 114:1708–1713. s://doi.org/10.1073/pnas.1620645114

Liu X, Ahn S, Kahsai AW, Meng KC, Latorraca NR, Pani B, Venkatakrishnan AJ, Masoudi A, Weis WI, Dror RO, Chen X, Lefkowitz RJ, Kobilka BK (2017) Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure. Nature 548:480–484. s://doi.org/10.1038/nature23652

Song G, Yang D, Wang Y, de Graaf C, Zhou Q, Jiang S, Liu K, Cai X, Dai A, Lin G, Liu D, Wu F, Wu Y, Zhao S, Ye L, Han GW, Lau J, Wu B, Hanson MA, Liu ZJ, Wang MW, Stevens RC (2017) Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature 546:312–315. s://doi.org/10.1038/nature22378

Oswald C, Rappas M, Kean J, Doré AS, Errey JC, Bennett K, Deflorian F, Christopher JA, Jazayeri A, Mason JS, Congreve M, Cooke RM, Marshall FH (2016) Intracellular allosteric antagonism of the CCR9 receptor. Nature 540:462–465. s://doi.org/10.1038/nature20606

Zheng Y, Qin L, Zacarías NV, de Vries H, Han GW, Gustavsson M, Dabros M, Zhao C, Cherney RJ, Carter P, Stamos D, Abagyan R, Cherezov V, Stevens RC, IJzerman AP, Heitman LH, Tebben A, Kufareva I, Handel TM (2016) Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 540:458–461. s://doi.org/10.1038/nature20605

Wakefield AE, Mason JS, Vajda S, Keserű GM (2019) Analysis of tractable allosteric sites in G protein-coupled receptors. Sci Rep 9:6180. s://doi.org/10.1038/s41598-019-42618-8

Renault P, Giraldo J (2020) Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors. Int J Mol Sci 22:187. s://doi.org/10.3390/ijms22010187

Covic L, Gresser AL, Talavera J, Swift S, Kuliopulos A (2002) Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides. Proc Natl Acad Sci U S A 99:643–648. s://doi.org/10.1073/pnas.022460899

Kuliopulos A, Covic L (2003) Blocking receptors on the inside: pepducin-based intervention of PAR signaling and thrombosis. Life Sci 74:255–262. s://doi.org/10.1016/j.lfs.2003.09.012

Miller J, Agarwal A, Devi LA, Fontanini K, Hamilton JA, Pin JP, Shields DC, Spek CA, Sakmar TP, Kuliopulos A, Hunt SW 3rd (2009) Insider access: pepducin symposium explores a new approach to GPCR modulation. Ann N Y Acad Sci 1180 Suppl 1:E1–E12. s://doi.org/10.1111/j.1749-6632.2009.05326.x

Tressel SL, Koukos G, Tchernychev B, Jacques SL, Covic L, Kuliopulos A (2011) Pharmacology, biodistribution, and efficacy of GPCR-based pepducins in disease models. Methods Mol Biol 683:259–275. s://doi.org/10.1007/978-1-60761-919-2_19

van Straten NC, Schoonus-Gerritsma GG, van Someren RG, Draaijer J, Adang AE, Timmers CM, Hanssen RG, van Boeckel CA (2002) The first orally active low molecular weight agonists for the LH receptor: thienopyr(im)idines with therapeutic potential for ovulation induction. Chembiochem 3:1023–1026. s://doi.org/10.1002/1439-7633(20021004)3:10<1023::AID-CBIC1023>3.0.CO;2-9

Moore S, Jaeschke H, Kleinau G, Neumann S, Costanzi S, Jiang JK, Childress J, Raaka BM, Colson A, Paschke R, Krause G, Thomas CJ, Gershengorn MC (2006) Evaluation of small-molecule modulators of the luteinizing hormone/choriogonadotropin and thyroid stimulating hormone receptors: structure-activity relationships and selective binding patterns. J Med Chem 49:3888–3896. s://doi.org/10.1021/jm060247s

Yanofsky SD, Shen ES, Holden F, Whitehorn E, Aguilar B, Tate E, Holmes CP, Scheuerman R, MacLean D, Wu MM, Frail DE, López FJ, Winneker R, Arey BJ, Barrett RW (2006) Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists. J Biol Chem 281:13226–13233. s://doi.org/10.1074/jbc.M600601200

Arey BJ, Yanofsky SD, Claudia Pérez M, Holmes CP, Wrobel J, Gopalsamy A, Stevis PE, López FJ, Winneker RC (2008) Differing pharmacological activities of thiazolidinone analogs at the FSH receptor. Biochem Biophys Res Commun 368:723–728. s://doi.org/10.1016/j.bbrc.2008.01.119

van Koppen CJ, Zaman GJ, Timmers CM, Kelder J, Mosselman S, van de Lagemaat R, Smit MJ, Hanssen RG (2008) A signaling-selective, nanomolar potent allosteric low molecular weight agonist for the human luteinizing hormone receptor. Naunyn Schmiedebergs Arch Pharmacol 378:503–514. s://doi.org/10.1007/s00210-008-0318-3

Ivetac A, McCammon JA (2010) Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach. Chem Biol Drug Des 76:201–217. s://doi.org/10.1111/j.1747-0285.2010.01012.x

Miao Y, Nichols SE, McCammon JA (2014) Mapping of allosteric druggable sites in activation-associated conformers of the M2 muscarinic receptor. Chem Biol Drug Des 83:237–246. s://doi.org/10.1111/cbdd.12233

Caliman AD, Miao Y, McCammon JA (2018) Mapping the allosteric sites of the A2A adenosine receptor. Chem Biol Drug Des 91:5–16. s://doi.org/10.1111/cbdd.13053

Wakefield AE, Bajusz D, Kozakov D, Keserű GM, Vajda S (2022) Conservation of Allosteric Ligand Binding Sites in G-Protein Coupled Receptors. J Chem Inf Model 62:4937–4954. s://doi.org/10.1021/acs.jcim.2c00209

Zhang D, Gao ZG, Zhang K, Kiselev E, Crane S, Wang J, Paoletta S, Yi C, Ma L, Zhang W, Han GW, Liu H, Cherezov V, Katritch V, Jiang H, Stevens RC, Jacobson KA, Zhao Q, Wu B (2015) Two disparate ligand-binding sites in the human P2Y1 receptor. Nature 520:317–321. s://doi.org/10.1038/nature14287

Cheng RKY, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Doré AS, Geschwindner S, Grebner C, Hermansson NO, Jazayeri A, Johansson P, Leong L, Prihandoko R, Rappas M, Soutter H, Snijder A, Sundström L, Tehan B, Thornton P, Troast D, Wiggin G, Zhukov A, Marshall FH, Dekker N (2017) Structural insight into allosteric modulation of protease-activated receptor 2. Nature 545:112–115. s://doi.org/10.1038/nature22309

Ciancetta A, O'Connor RD, Paoletta S, Jacobson KA (2017) Demystifying P2Y1 Receptor Ligand Recognition through Docking and Molecular Dynamics Analyses. J Chem Inf Model 57:3104–3123. s://doi.org/10.1021/acs.jcim.7b00528

Ciancetta A, Gill AK, Ding T, Karlov DS, Chalhoub G, McCormick PJ, Tikhonova IG (2021) Probe Confined Dynamic Mapping for G Protein-Coupled Receptor Allosteric Site Prediction. ACS Cent Sci 7:1847–1862. s://doi.org/10.1021/acscentsci.1c00802

Jiménez-Rosés M, Matsoukas MT, Caltabiano G, Cordomí A (2018) Ligand-Triggered Structural Changes in the M2 Muscarinic Acetylcholine Receptor. J Chem Inf Model 58:1074–1082. s://doi.org/10.1021/acs.jcim.8b00108

Shao Z, Yan W, Chapman K, Ramesh K, Ferrell AJ, Yin J, Wang X, Xu Q, Rosenbaum DM (2019) Structure of an allosteric modulator bound to the CB1 cannabinoid receptor. Nat Chem Biol 15:1199–1205. s://doi.org/10.1038/s41589-019-0387-2

Atanasio S, Deganutti G, Reynolds CA (2020) Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics. J Comput Aided Mol Des 34:1181–1193. s://doi.org/10.1007/s10822-020-00338-6

Bueno AB, Sun B, Willard FS, Feng D, Ho JD, Wainscott DB, Showalter AD, Vieth M, Chen Q, Stutsman C, Chau B, Ficorilli J, Agejas FJ, Cumming GR, Jiménez A, Rojo I, Kobilka TS, Kobilka BK, Sloop KW (2020) Structural insights into probe-dependent positive allosterism of the GLP-1 receptor. Nat Chem Biol 16:1105–1110. s://doi.org/10.1038/s41589-020-0589-7

Teng D, Chen J, Li D, Wu Z, Li W, Tang Y, Liu G (2020) Computational Insights into Molecular Activation and Positive Cooperative Mechanisms of FFAR1 Modulators. J Chem Inf Model 60:3214–3230. s://doi.org/10.1021/acs.jcim.0c00030

Ding T, Karlov DS, Pino-Angeles A, Tikhonova IG (2022) Intermolecular Interactions in G Protein-Coupled Receptor Allosteric Sites at the Membrane Interface from Molecular Dynamics Simulations and Quantum Chemical Calculations. J Chem Inf Model 62:4736–4747. s://doi.org/10.1021/acs.jcim.2c00788

Jazayeri A, Doré AS, Lamb D, Krishnamurthy H, Southall SM, Baig AH, Bortolato A, Koglin M, Robertson NJ, Errey JC, Andrews SP, Teobald I, Brown AJ, Cooke RM, Weir M, Marshall FH (2016) Extra-helical binding site of a glucagon receptor antagonist. Nature 533:274–277. s://doi.org/10.1038/nature17414

Lu J, Byrne N, Wang J, Bricogne G, Brown FK, Chobanian HR, Colletti SL, Di Salvo J, Thomas-Fowlkes B, Guo Y, Hall DL, Hadix J, Hastings NB, Hermes JD, Ho T, Howard AD, Josien H, Kornienko M, Lumb KJ, Miller MW, Patel SB, Pio B, Plummer CW, Sherborne BS, Sheth P, Souza S, Tummala S, Vonrhein C, Webb M, Allen SJ, Johnston JM, Weinglass AB, Sharma S, Soisson SM (2017) Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat Struct Mol Biol 24:570–577. https://doi.org/10.1038/nsmb.3417

Liu H, Kim HR, Deepak RNVK, Wang L, Chung KY, Fan H, Wei Z, Zhang C (2018) Orthosteric and allosteric action of the C5a receptor antagonists. Nat Struct Mol Biol 25:472–481. s://doi.org/10.1038/s41594-018-0067-z

Robertson N, Rappas M, Doré AS, Brown J, Bottegoni G, Koglin M, Cansfield J, Jazayeri A, Cooke RM, Marshall FH (2018) Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727. Nature 553:111–114. s://doi.org/10.1038/nature25025.

Liu X, Kaindl J, Korczynska M, Stößel A, Dengler D, Stanek M, Hübner H, Clark MJ, Mahoney J, Matt RA, Xu X, Hirata K, Shoichet BK, Sunahara RK, Kobilka BK, Gmeiner P (2020) An allosteric modulator binds to a conformational hub in the β2 adrenergic receptor. Nat Chem Biol 16:749–755. s://doi.org/10.1038/s41589-020-0549-2

Zhuang Y, Krumm B, Zhang H, Zhou XE, Wang Y, Huang XP, Liu Y, Cheng X, Jiang Y, Jiang H, Zhang C, Yi W, Roth BL, Zhang Y, Xu HE (2021) Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor. Cell Res 31:593–596. https://doi.org/10.1038/s41422-021-00482-0

Draper-Joyce CJ, Bhola R, Wang J, Bhattarai A, Nguyen ATN, Cowie-Kent I, O'Sullivan K, Chia LY, Venugopal H, Valant C, Thal DM, Wootten D, Panel N, Carlsson J, Christie MJ, White PJ, Scammells P, May LT, Sexton PM, Danev R, Miao Y, Glukhova A, Imlach WL, Christopoulos A (2021) Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia. Nature 597:571–576. s://doi.org/10.1038/s41586-021-03897-2

Dawaliby R, Trubbia C, Delporte C, Masureel M, Van Antwerpen P, Kobilka BK, Govaerts C (2016) Allosteric regulation of G protein-coupled receptor activity by phospholipids. Nat Chem Biol 12:35–39. s://doi.org/10.1038/nchembio.1960

Yen HY, Hoi KK, Liko I, Hedger G, Horrell MR, Song W, Wu D, Heine P, Warne T, Lee Y, Carpenter B, Plückthun A, Tate CG, Sansom MSP, Robinson CV (2018) PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling. Nature 559:423–427. s://doi.org/10.1038/s41586-018-0325-6

Jafurulla M, Aditya Kumar G, Rao BD, Chattopadhyay A (2019) A Critical Analysis of Molecular Mechanisms Underlying Membrane Cholesterol Sensitivity of GPCRs. Adv Exp Med Biol 1115:21–52. s://doi.org/10.1007/978-3-030-04278-3_2

Lu S, He X, Yang Z, Chai Z, Zhou S, Wang J, Rehman AU, Ni D, Pu J, Sun J, Zhang J (2021) Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design. Nat Commun 12:4721. s://doi.org/10.1038/s41467-021-25020-9

Chan WKB, Carlson HA, Traynor JR (2023) Application of Mixed-Solvent Molecular Dynamics Simulations for Prediction of Allosteric Sites on G Protein-Coupled Receptors. Mol Pharmacol 103:274–285. s://doi.org/10.1124/molpharm.122.000612

Shen S, Zhao C, Wu C, Sun S, Li Z, Yan W, Shao Z (2023) Allosteric modulation of G protein-coupled receptor signaling. Front Endocrinol (Lausanne) 14:1137604. s://doi.org/10.3389/fendo.2023.1137604

Chaturvedi M, Maharana J, Shukla AK (2020) Terminating G-Protein Coupling: Structural Snapshots of GPCR-β-Arrestin Complexes. Cell 180:1041–1043. s://doi.org/10.1016/j.cell.2020.02.047

DeVree BT, Mahoney JP, Vélez-Ruiz GA, Rasmussen SG, Kuszak AJ, Edwald E, Fung JJ, Manglik A, Masureel M, Du Y, Matt RA, Pardon E, Steyaert J, Kobilka BK, Sunahara RK (2016) Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature 535:182–186. s://doi.org/10.1038/nature18324

Ahn D, Chung KY (2022) The Conformational Dynamics of Heterotrimeric G Proteins During GPCR-Mediated Activation. Subcell Biochem 99:271–284. s://doi.org/10.1007/978-3-031-00793-4_8

Mafi A, Kim SK, Goddard WA 3rd (2022) The mechanism for ligand activation of the GPCR-G protein complex. Proc Natl Acad Sci U S A 119:e2110085119. s://doi.org/10.1073/pnas.2110085119

Bourne HR (1997) How receptors talk to trimeric G proteins. Curr Opin Cell Biol 9:134–142. s://doi.org/10.1016/s0955-0674(97)80054-3

Quist E, Satumtira N, Vasan R (1999) Regulation of guanine nucleotide turnover on Gi/Go by agonist-stimulated and spontaneously active muscarinic receptors in cardiac membranes. Arch Biochem Biophys 361:57–64. s://doi.org/10.1006/abbi.1998.0945

Hamm HE (2001) How activated receptors couple to G proteins. Proc Natl Acad Sci U S A 98:4819–4821. s://doi.org/10.1073/pnas.011099798

Vetter IR, Wittinghofer A (2001) The guanine nucleotide-binding switch in three dimensions. Science 294:1299–1304. s://doi.org/10.1126/science.1062023

Hein P, Frank M, Hoffmann C, Lohse MJ, Bünemann M (2005) Dynamics of receptor/G protein coupling in living cells. EMBO J 24:4106–4114. s://doi.org/10.1038/sj.emboj.7600870

Leurs R, Smit MJ, Alewijnse AE, Timmerman H (1998) Agonist-independent regulation of constitutively active G-protein-coupled receptors. Trends Biochem Sci 23:418–422. s://doi.org/10.1016/s0968-0004(98)01287-0

Seifert R, Wenzel-Seifert K (2002) Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch Pharmacol 366:381–416. s://doi.org/10.1007/s00210-002-0588-0

Zhou B, Hall DA, Giraldo J (2019) Can Adding Constitutive Receptor Activity Redefine Biased Signaling Quantification? Trends Pharmacol Sci 40:156–160. https://doi.org/10.1016/j.tips.2019.01.002

Ceraudo E, Horioka M, Mattheisen JM, Hitchman TD, Moore AR, Kazmi MA, Chi P, Chen Y, Sakmar TP, Huber T (2021) Direct evidence that the GPCR CysLTR2 mutant causative of uveal melanoma is constitutively active with highly biased signaling. J Biol Chem 296:100163. s://doi.org/10.1074/jbc.RA120.015352

Nobles M, Benians A, Tinker A (2005) Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells. Proc Natl Acad Sci U S A 102:18706–18711. s://doi.org/10.1073/pnas.0504778102

Ayoub MA, Maurel D, Binet V, Fink M, Prézeau L, Ansanay H, Pin JP (2007) Real-time analysis of agonist-induced activation of protease-activated receptor 1/Galphai1 protein complex measured by bioluminescence resonance energy transfer in living cells. Mol Pharmacol 71:1329–1340. s://doi.org/10.1124/mol.106.030304

Qin K, Dong C, Wu G, Lambert NA (2011) Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers. Nat Chem Biol 7:740–747. s://doi.org/10.1038/nchembio.642

García-Nafría J, Tate CG (2019) Cryo-EM structures of GPCRs coupled to Gs, Gi and Go. Mol Cell Endocrinol 488:1–13. s://doi.org/10.1016/j.mce.2019.02.006

Ulsund AH, Dahl M, Frimurer TM, Manfra O, Schwartz TW, Levy FO, Andressen KW (2019) Preassociation between the 5-HT7 serotonin receptor and G protein Gs: molecular determinants and association with low potency activation of adenylyl cyclase. FASEB J 33:3870–3886. s://doi.org/10.1096/fj.201800805RR

Jang W, Adams CE, Liu H, Zhang C, Levy FO, Andressen KW, Lambert NA (2020) An inactive receptor-G protein complex maintains the dynamic range of agonist-induced signaling. Proc Natl Acad Sci U S A 117:30755–30762. s://doi.org/10.1073/pnas.2010801117

Andressen KW, Ulsund AH, Krobert KA, Lohse MJ, Bünemann M, Levy FO (2018) Related GPCRs couple differently to Gs: preassociation between G protein and 5-HT7 serotonin receptor reveals movement of Gαs upon receptor activation. FASEB J 32:1059–1069. s://doi.org/10.1096/fj.201700486R

Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS, Devree BT, Rosenbaum DM, Thian FS, Kobilka TS, Schnapp A, Konetzki I, Sunahara RK, Gellman SH, Pautsch A, Steyaert J, Weis WI, Kobilka BK (2011) Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. Nature 2011 469:175–180. s://doi.org/10.1038/nature09648

Ring AM, Manglik A, Kruse AC, Enos MD, Weis WI, Garcia KC, Kobilka BK (2013) Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody. Nature 502:575–579. s://doi.org/10.1038/nature12572

Staus DP, Strachan RT, Manglik A, Pani B, Kahsai AW, Kim TH, Wingler LM, Ahn S, Chatterjee A, Masoudi A, Kruse AC, Pardon E, Steyaert J, Weis WI, Prosser RS, Kobilka BK, Costa T, Lefkowitz RJ (2016) Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation. Nature 535:448–452. https://doi.org/10.1038/nature18636

Lee Y, Warne T, Nehmé R, Pandey S, Dwivedi-Agnihotri H, Chaturvedi M, Edwards PC, García-Nafría J, Leslie AGW, Shukla AK, Tate CG (2020) Molecular basis of β-arrestin coupling to formoterol-bound β1-adrenoceptor. Nature 583:862–866. s://doi.org/10.1038/s41586-020-2419-1

Gurevich VV, Pals-Rylaarsdam R, Benovic JL, Hosey MM, Onorato JJ (1997) Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity. J Biol Chem 272:28849–28852. s://doi.org/10.1074/jbc.272.46.28849

Gurevich VV, Dion SB, Onorato JJ, Ptasienski J, Kim CM, Sterne-Marr R, Hosey MM, Benovic J (1995) Arrestin interactions with G protein-coupled receptors. Direct binding studies of wild type and mutant arrestins with rhodopsin, beta 2-adrenergic, and m2 muscarinic cholinergic receptors. J Biol Chem 270:720–731. s://doi.org/10.1074/jbc.270.2.720

Kumari P, Srivastava A, Banerjee R, Ghosh E, Gupta P, Ranjan R, Chen X, Gupta B, Gupta C, Jaiman D, Shukla AK (2016) Functional competence of a partially engaged GPCR-β-arrestin complex. Nat Commun 7:13416. s://doi.org/10.1038/ncomms13416

Cahill TJ 3rd, Thomsen AR, Tarrasch JT, Plouffe B, Nguyen AH, Yang F, Huang LY, Kahsai AW, Bassoni DL, Gavino BJ, Lamerdin JE, Triest S, Shukla AK, Berger B, Little J 4th, Antar A, Blanc A, Qu CX, Chen X, Kawakami K, Inoue A, Aoki J, Steyaert J, Sun JP, Bouvier M, Skiniotis G, Lefkowitz RJ (2017) Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis. Proc Natl Acad Sci U S A 114:2562–2567. s://doi.org/10.1073/pnas.1701529114

Nguyen AH, Lefkowitz RJ (2021) Signaling at the endosome: cryo-EM structure of a GPCR-G protein-beta-arrestin megacomplex. FEBS J 288:2562–2569. s://doi.org/10.1111/febs.15773

Wehbi VL, Stevenson HP, Feinstein TN, Calero G, Romero G, Vilardaga JP (2013) Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gβγ complex. Proc Natl Acad Sci U S A 110:1530–1535. s://doi.org/10.1073/pnas.1205756110

Thomsen ARB, Plouffe B, Cahill TJ 3rd, Shukla AK, Tarrasch JT, Dosey AM, Kahsai AW, Strachan RT, Pani B, Mahoney JP, Huang L, Breton B, Heydenreich FM, Sunahara RK, Skiniotis G, Bouvier M, Lefkowitz RJ (2016) GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling. Cell 166:907–919. s://doi.org/10.1016/j.cell.2016.07.004

Cheloha RW, Gellman SH, Vilardaga JP, Gardella TJ (2015) PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol 11:712–724. s://doi.org/10.1038/nrendo.2015.139

Baidya M, Chaturvedi M, Dwivedi-Agnihotri H, Ranjan A, Devost D, Namkung Y, Stepniewski TM, Pandey S, Baruah M, Panigrahi B, Sarma P, Yadav MK, Maharana J, Banerjee R, Kawakami K, Inoue A, Selent J, Laporte SA, Hébert TE, Shukla AK (2022) Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody. Nat Commun 13:4634. s://doi.org/10.1038/s41467-022-32386-x

Dwivedi-Agnihotri H, Chaturvedi M, Baidya M, Stepniewski TM, Pandey S, Maharana J, Srivastava A, Caengprasath N, Hanyaloglu AC, Selent J, Shukla AK (2020) Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling. Sci Adv 6:eabb8368. s://doi.org/10.1126/sciadv.abb8368

Beautrait A, Paradis JS, Zimmerman B, Giubilaro J, Nikolajev L, Armando S, Kobayashi H, Yamani L, Namkung Y, Heydenreich FM, Khoury E, Audet M, Roux PP, Veprintsev DB, Laporte SA, Bouvier M (2017) A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling. Nat Commun 8:15054. s://doi.org/10.1038/ncomms15054

Violin JD, Dewire SM, Barnes WG, Lefkowitz RJ (2006) G protein-coupled receptor kinase and beta-arrestin-mediated desensitization of the angiotensin II type 1A receptor elucidated by diacylglycerol dynamics. J Biol Chem 281:36411–36419. s://doi.org/10.1074/jbc.M607956200

Smith JS, Lefkowitz RJ, Rajagopal S (2018) Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov 17:243–260. s://doi.org/10.1038/nrd.2017.229

Li A, Liu S, Huang R, Ahn S, Lefkowitz RJ (2023) Loss of biased signaling at a G protein-coupled receptor in overexpressed systems. PLoS One 18:e0283477. s://doi.org/10.1371/journal.pone.0283477

Kotliar IB, Lorenzen E, Schwenk JM, Hay DL, Sakmar TP (2023) Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins. Pharmacol Rev 75:1–34. s://doi.org/10.1124/pharmrev.120.000180

Klein KR, Matson BC, Caron KM (2016) The expanding repertoire of receptor activity modifying protein (RAMP) function. Crit Rev Biochem Mol Biol 51:65–71. s://doi.org/10.3109/10409238.2015.1128875

Pioszak AA, Hay DL (2020) RAMPs as allosteric modulators of the calcitonin and calcitonin-like class B G protein-coupled receptors. Adv Pharmacol 88:115–141. s://doi.org/10.1016/bs.apha.2020.01.001

Bouschet T, Martin S, Henley JM (2005) Receptor-activity-modifying proteins are required for forward trafficking of the calcium-sensing receptor to the plasma membrane. J Cell Sci 118(Pt 20):4709–4720. s://doi.org/10.1242/jcs.02598

Hay DL, Pioszak AA (2016) Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles. Annu Rev Pharmacol Toxicol 56:469–487. s://doi.org/10.1146/annurev-pharmtox-010715-103120

Udawela M, Christopoulos G, Tilakaratne N, Christopoulos A, Albiston A, Sexton PM (2006) Distinct receptor activity-modifying protein domains differentially modulate interaction with calcitonin receptors. Mol Pharmacol 69:1984–1989. s://doi.org/10.1124/mol.105.021915

Sexton PM, Poyner DR, Simms J, Christopoulos A, Hay DL (2009) Modulating receptor function through RAMPs: can they represent drug targets in themselves? Drug Discov Today 14:413–419. s://doi.org/10.1016/j.drudis.2008.12.009

Arrigoni S, Le Foll C, Cabak A, Lundh S, Raun K, John LM, Lutz TA (2021) A selective role for receptor activity-modifying proteins in subchronic action of the amylin selective receptor agonist NN1213 compared with salmon calcitonin on body weight and food intake in male mice. Eur J Neurosci 54:4863–4876. s://doi.org/10.1111/ejn.15376

Wootten D, Lindmark H, Kadmiel M, Willcockson H, Caron KM, Barwell J, Drmota T, Poyner DR (2013) Receptor activity modifying proteins (RAMPs) interact with the VPAC2 receptor and CRF1 receptors and modulate their function. Br J Pharmacol 168:822–834. s://doi.org/10.1111/j.1476-5381.2012.02202.x

Christopoulos A, Christopoulos G, Morfis M, Udawela M, Laburthe M, Couvineau A, Kuwasako K, Tilakaratne N, Sexton PM (2003) Novel receptor partners and function of receptor activity-modifying proteins. J Biol Chem 278:3293–3297. s://doi.org/10.1074/jbc.C200629200

Morfis M, Tilakaratne N, Furness SG, Christopoulos G, Werry TD, Christopoulos A, Sexton PM (2008) Receptor activity-modifying proteins differentially modulate the G protein-coupling efficiency of amylin receptors. Endocrinology 149:5423–5431. https://doi.org/10.1210/en.2007-1735

Shao L, Chen Y, Zhang S, Zhang Z, Cao Y, Yang D, Wang MW (2022) Modulating effects of RAMPs on signaling profiles of the glucagon receptor family. Acta Pharm Sin B 12:637–650. s://doi.org/10.1016/j.apsb.2021.07.028

Krishna Kumar K, O'Brien ES, Habrian CH, Latorraca NR, Wang H, Tuneew I, Montabana E, Marqusee S, Hilger D, Isacoff EY, Mathiesen JM, Kobilka BK (2023) Negative allosteric modulation of the glucagon receptor by RAMP2. Cell 186:1465–1477.e18. s://doi.org/10.1016/j.cell.2023.02.028

Kadmiel M, Fritz-Six KL, Caron KM (2012) Understanding RAMPs through genetically engineered mouse models. Adv Exp Med Biol 744:49–60. s://doi.org/10.1007/978-1-4614-2364-5_5

Lenhart PM, Broselid S, Barrick CJ, Leeb-Lundberg LM, Caron KM (2013) G-protein-coupled receptor 30 interacts with receptor activity-modifying protein 3 and confers sex-dependent cardioprotection. J Mol Endocrinol 51:191–202. s://doi.org/10.1530/JME-13-0021

Li M, Wetzel-Strong SE, Hua X, Tilley SL, Oswald E, Krummel MF, Caron KM (2014) Deficiency of RAMP1 attenuates antigen-induced airway hyperresponsiveness in mice. PLoS One 9:e102356. s://doi.org/10.1371/journal.pone.0102356

Pawlak JB, Wetzel-Strong SE, Dunn MK, Caron KM (2017) Cardiovascular effects of exogenous adrenomedullin and CGRP in Ramp and Calcrl deficient mice. Peptides 88:1–7. s://doi.org/10.1016/j.peptides.2016.12.002

Shindo T, Tanaka M, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Yamauchi A, Sakurai T (2019) Regulation of cardiovascular development and homeostasis by the adrenomedullin-RAMP system. Peptides 111:55–61. s://doi.org/10.1016/j.peptides.2018.04.004

Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Tanaka M, Wei Y, Kakihara S, Zhao Y, Aruga K, Kawagishi H, Nakada T, Yamada M, Shindo T (2021) Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress. Endocrinology 162(3):bqab001. s://doi.org/10.1210/endocr/bqab001.

Wootten DL, Simms J, Hay DL, Christopoulos A, Sexton PM (2010) Receptor activity modifying proteins and their potential as drug targets. Prog Mol Biol Transl Sci 91:53–79. s://doi.org/10.1016/S1877-1173(10)91003-X

Sexton PM, Poyner DR, Simms J, Christopoulos A, Hay DL (2012) RAMPs as drug targets. Adv Exp Med Biol 744:61–74. s://doi.org/10.1007/978-1-4614-2364-5_6

Sixt ML, Messlinger K, Fischer MJ (2009) Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus. Brain 132:3134–3141. s://doi.org/10.1093/brain/awp168

ter Haar E, Koth CM, Abdul-Manan N, Swenson L, Coll JT, Lippke JA, Lepre CA, Garcia-Guzman M, Moore JM (2010) Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism. Structure 18:1083–1093. s://doi.org/10.1016/j.str.2010.05.014

Greco R, Demartini C, Francavilla M, Zanaboni AM, Tassorelli C (2022) Antagonism of CGRP Receptor: Central and Peripheral Mechanisms and Mediators in an Animal Model of Chronic Migraine. Cells 11:3092. s://doi.org/10.3390/cells11193092

Russo AF, Hay DL (2023) CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond. Physiol Rev 103:1565–1644 s://doi.org/10.1152/physrev.00059.2021

Cooray SN, Chan L, Webb TR, Metherell L, Clark AJ (2009) Accessory proteins are vital for the functional expression of certain G protein-coupled receptors. Mol Cell Endocrinol 300:17–24. s://doi.org/10.1016/j.mce.2008.10.004

Roux BT, Cottrell GS (2014) G protein-coupled receptors: what a difference a 'partner' makes. Int J Mol Sci 15:1112–1142. s://doi.org/10.3390/ijms15011112

Tao YX (2020) Molecular chaperones and G protein-coupled receptor maturation and pharmacology. Mol Cell Endocrinol 511:110862. s://doi.org/10.1016/j.mce.2020.110862

Yu T, Su X, Pan Y, Zhuang H (2017) Receptor-transporting protein (RTP) family members play divergent roles in the functional expression of odorant receptors. PLoS One 12(6):e0179067. s://doi.org/10.1371/journal.pone.0179067

Fukutani Y, Tamaki R, Inoue R, Koshizawa T, Sakashita S, Ikegami K, Ohsawa I, Matsunami H, Yohda M (2019) The N-terminal region of RTP1S plays important roles in dimer formation and odorant receptor-trafficking. J Biol Chem 294:14661–14673. s://doi.org/10.1074/jbc.RA118.007110

Behrens M, Bartelt J, Reichling C, Winnig M, Kuhn C, Meyerhof W (2006) Members of RTP and REEP gene families influence functional bitter taste receptor expression. J Biol Chem 281:20650–20659. s://doi.org/10.1074/jbc.M513637200

Décaillot FM, Rozenfeld R, Gupta A, Devi LA (2008) Cell surface targeting of mu-delta opioid receptor heterodimers by RTP4. Proc Natl Acad Sci U S A 105:16045–16050. s://doi.org/10.1073/pnas.0804106105

Wu L, Pan Y, Chen GQ, Matsunami H, Zhuang H (2012) Receptor-transporting protein 1 short (RTP1S) mediates translocation and activation of odorant receptors by acting through multiple steps. J Biol Chem 287:22287–22294. s://doi.org/10.1074/jbc.M112.345884

Björk S, Hurt CM, Ho VK, Angelotti T (2013) REEPs are membrane shaping adapter proteins that modulate specific g protein-coupled receptor trafficking by affecting ER cargo capacity. PLoS One 8:e76366. s://doi.org/10.1371/journal.pone.0076366

Fan S, Liu H, Li L (2022) The REEP family of proteins: Molecular targets and role in pathophysiology. Pharmacol Res 185:106477. s://doi.org/10.1016/j.phrs.2022.106477

Routledge SJ, Simms J, Clark A, Yeung HY, Wigglesworth MJ, Dickerson IM, Kitchen P, Ladds G, Poyner DR (2020) Receptor component protein, an endogenous allosteric modulator of family B G protein coupled receptors. Biochim Biophys Acta Biomembr 1862:183174. s://doi.org/10.1016/j.bbamem.2019.183174

Hay DL, Garelja ML, Poyner DR, Walker CS (2018) Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol 175:3–17. s://doi.org/10.1111/bph.14075

Egea SC, Dickerson IM (2012) Direct interactions between calcitonin-like receptor (CLR) and CGRP-receptor component protein (RCP) regulate CGRP receptor signaling. Endocrinology 153:1850–1860. s://doi.org/10.1210/en.2011-1459

Berruien NNA, Smith CL (2020) Emerging roles of melanocortin receptor accessory proteins (MRAP and MRAP2) in physiology and pathophysiology. Gene 757:144949. s://doi.org/10.1016/j.gene.2020.144949

Metherell LA, Chapple JP, Cooray S, David A, Becker C, Rüschendorf F, Naville D, Begeot M, Khoo B, Nürnberg P, Huebner A, Cheetham ME, Clark AJ (2005) Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet 37:166–170. s://doi.org/10.1038/ng1501

Chan LF, Webb TR, Chung TT, Meimaridou E, Cooray SN, Guasti L, Chapple JP, Egertová M, Elphick MR, Cheetham ME, Metherell LA, Clark AJ (2009) MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. Proc Natl Acad Sci U S A 106:6146–6151. s://doi.org/10.1073/pnas.0809918106

Sebag JA, Hinkle PM (2007) Melanocortin-2 receptor accessory protein MRAP forms antiparallel homodimers. Proc Natl Acad Sci U S A 104:20244–20249. s://doi.org/10.1073/pnas.0708916105

Ji RL, Jiang SS, Tao YX (2022) Modulation of Canine Melanocortin-3 and -4 Receptors by Melanocortin-2 Receptor Accessory Protein 1 and 2. Biomolecules 12:1608. s://doi.org/10.3390/biom12111608

van der Westhuizen ET, Valant C, Sexton PM, Christopoulos A (2015) Endogenous allosteric modulators of G protein-coupled receptors. J Pharmacol Exp Ther 353:246–260. s://doi.org/10.1124/jpet.114.221606

White KL, Eddy MT, Gao ZG, Han GW, Lian T, Deary A, Patel N, Jacobson KA, Katritch V, Stevens RC (2018) Structural Connection between Activation Microswitch and Allosteric Sodium Site in GPCR Signaling. Structure 26:259-269.e5. s://doi.org/10.1016/j.str.2017.12.013

Ye L, Neale C, Sljoka A, Lyda B, Pichugin D, Tsuchimura N, Larda ST, Pomès R, García AE, Ernst OP, Sunahara RK, Prosser RS (2018) Mechanistic insights into allosteric regulation of the A2A adenosine G protein-coupled receptor by physiological cations. Nat Commun 9:1372. s://doi.org/10.1038/s41467-018-03314-9

Satała G, Duszyńska B, Stachowicz K, Rafalo A, Pochwat B, Luckhart C, Albert PR, Daigle M, Tanaka KF, Hen R, Lenda T, Nowak G, Bojarski AJ, Szewczyk B (2016) Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies. Mol Neurobiol 53:6869–6881. s://doi.org/10.1007/s12035-015-9586-3

Link R, Veiksina S, Tahk MJ, Laasfeld T, Paiste P, Kopanchuk S, Rinken A (2020) The constitutive activity of melanocortin-4 receptors in cAMP pathway is allosterically modulated by zinc and copper ions. J Neurochem 153:346–361. s://doi.org/10.1111/jnc.14933

Jiang W, Zheng S (2022) Structural insights into galanin receptor signaling. Proc Natl Acad Sci U S A 119:e2121465119. s://doi.org/10.1073/pnas.2121465119

Pert CB, Snyder SH (1973) Properties of opiate-receptor binding in rat brain. Proc Natl Acad Sci U S A 70:2243–2247. s://doi.org/10.1073/pnas.70.8.2243

Appelmans N, Carroll JA, Rance MJ, Simon EJ, Traynor JR (1986) Sodium ions increase the binding of the antagonist peptide ICI 174864 to the delta-opiate receptor. Neuropeptides 7:139–143. s://doi.org/10.1016/0143-4179(86)90089-2

Simon EJ, Groth J (1975) Kinetics of opiate receptor inactivation by sulfhydryl reagents: evidence for conformational change in presence of sodium ions. Proc Natl Acad Sci U S A 72:2404–2407. s://doi.org/10.1073/pnas.72.6.2404

Fraser CM, Wang CD, Robinson DA, Gocayne JD, Venter JC (1989) Site-directed mutagenesis of m1 muscarinic acetylcholine receptors: conserved aspartic acids play important roles in receptor function. Mol Pharmacol 36:840–847.

Horstman DA, Brandon S, Wilson AL, Guyer CA, Cragoe EJ Jr, Limbird LE (1990) An aspartate conserved among G-protein receptors confers allosteric regulation of alpha 2-adrenergic receptors by sodium. J Biol Chem 265:21590–21595.

Neve KA (1991) Regulation of dopamine D2 receptors by sodium and pH. Mol Pharmacol 39:570–578.

Strader CD, Fong TM, Tota MR, Underwood D, Dixon RA (1994) Structure and function of G protein-coupled receptors. Annu Rev Biochem 63:101–132. s://doi.org/10.1146/annurev.bi.63.070194.000533

Katritch V, Fenalti G, Abola EE, Roth BL, Cherezov V, Stevens RC (2014) Allosteric sodium in class A GPCR signaling. Trends Biochem Sci 39:233–244. s://doi.org/10.1016/j.tibs.2014.03.002

Massink A, Gutiérrez-de-Terán H, Lenselink EB, Ortiz Zacarías NV, Xia L, Heitman LH, Katritch V, Stevens RC, IJzerman AP (2015) Sodium ion binding pocket mutations and adenosine A2A receptor function. Mol Pharmacol 87:305–313. s://doi.org/10.1124/mol.114.095737

Zarzycka B, Zaidi SA, Roth BL, Katritch V (2019) Harnessing Ion-Binding Sites for GPCR Pharmacology. Pharmacol Rev 71:571–595. s://doi.org/10.1124/pr.119.017863

Fenalti G, Giguere PM, Katritch V, Huang XP, Thompson AA, Cherezov V, Roth BL, Stevens RC (20114) Molecular control of δ-opioid receptor signalling. Nature 506:191–196. s://doi.org/10.1038/nature12944

Sun X, Laroche G, Wang X, Ågren H, Bowman GR, Giguère PM, Tu Y (2017) Propagation of the Allosteric Modulation Induced by Sodium in the δ-Opioid Receptor. Chemistry 23:4615–4624. s://doi.org/10.1002/chem.201605575

Mohamud AO, Zeghal M, Patel S, Laroche G, Blgacim N, Giguère PM (2022) Functional Characterization of Sodium Channel Inhibitors at the Delta-Opioid Receptor. ACS Omega 7:16939–16951. s://doi.org/10.1021/acsomega.1c07226

Selent J, Sanz F, Pastor M, De Fabritiis G (2010) Induced effects of sodium ions on dopaminergic G-protein coupled receptors. PLoS Comput Biol 6:e1000884. s://doi.org/10.1371/journal.pcbi.1000884

Miller-Gallacher JL, Nehmé R, Warne T, Edwards PC, Schertler GF, Leslie AG, Tate CG (2014) The 2.1 Å resolution structure of cyanopindolol-bound β1-adrenoceptor identifies an intramembrane Na+ ion that stabilises the ligand-free receptor. PLoS One 9:e92727. s://doi.org/10.1371/journal.pone.0092727

Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, IJzerman AP, Cherezov V, Stevens RC (2012) Structural basis for allosteric regulation of GPCRs by sodium ions. Science 337:232–236. s://doi.org/10.1126/science.1219218

Zhang C, Srinivasan Y, Arlow DH, Fung JJ, Palmer D, Zheng Y, Green HF, Pandey A, Dror RO, Shaw DE, Weis WI, Coughlin SR, Kobilka BK (2012) High-resolution crystal structure of human protease-activated receptor 1. Nature 492:387–392. s://doi.org/10.1038/nature11701

Agasid MT, Sørensen L, Urner LH, Yan J, Robinson CV (2021) The Effects of Sodium Ions on Ligand Binding and Conformational States of G Protein-Coupled Receptors-Insights from Mass Spectrometry. J Am Chem Soc 143:4085–4089. s://doi.org/10.1021/jacs.0c11837

Vickery ON, Carvalheda CA, Zaidi SA, Pisliakov AV, Katritch V, Zachariae U (2018) Intracellular Transfer of Na+ in an Active-State G-Protein-Coupled Receptor. Structure 26:171-180.e2. s://doi.org/10.1016/j.str.2017.11.013

Zhorov BS, Ananthanarayanan VS (1998) Signal transduction within G-protein coupled receptors via an ion tunnel: a hypothesis. J Biomol Struct Dyn 15:631–637. s://doi.org/10.1080/07391102.1998.10508980

Zhorov BS, Ananthanarayanan VS (2000) Homology models of mu-opioid receptor with organic and inorganic cations at conserved aspartates in the second and third transmembrane domains. Arch Biochem Biophys 375:31–49. s://doi.org/10.1006/abbi.1999.1529

Chauhan A, Singh J, Sangwan N, Dhawan R, Avti PK (2023) An Atomic Level Investigation of Sodium Ions Regulating Agonist and Antagonist Binding in the Active Site of a Novel Target 5HT2BR Against Drug-Resistant Epilepsy. Cell Biochem Biophys 81:253–267. s://doi.org/10.1007/s12013-023-01143-2

Chan HCS, Xu Y, Tan L, Vogel H, Cheng J, Wu D, Yuan S (2020) Enhancing the Signaling of GPCRs via Orthosteric Ions. ACS Cent Sci 6:274–282. s://doi.org/10.1021/acscentsci.9b01247

Ericksen SS, Cummings DF, Weinstein H, Schetz JA (2009) Ligand selectivity of D2 dopamine receptors is modulated by changes in local dynamics produced by sodium binding. J Pharmacol Exp Ther 328:40–54. s://doi.org/10.1124/jpet.108.141531

Livingston KE, Traynor JR (2014) Disruption of the Na+ ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor. Proc Natl Acad Sci U S A 111:18369–18374. s://doi.org/10.1073/pnas.1415013111

Draper-Joyce CJ, Verma RK, Michino M, Shonberg J, Kopinathan A, Klein Herenbrink C, Scammells PJ, Capuano B, Abramyan AM, Thal DM, Javitch JA, Christopoulos A, Shi L, Lane JR (2018) The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions. Sci Rep 8:1208. s://doi.org/10.1038/s41598-018-19642-1

Wang S, Wacker D, Levit A, Che T, Betz RM, McCorvy JD, Venkatakrishnan AJ, Huang XP, Dror RO, Shoichet BK, Roth BL (2017) D4 dopamine receptor high-resolution structures enable the discovery of selective agonists. Science 358:381–386. s://doi.org/10.1126/science.aan5468

Tauber M, Ben Chaim Y (2022) The activity of the serotonergic 5-HT1A receptor is modulated by voltage and sodium levels. J Biol Chem 298:101978. s://doi.org/10.1016/j.jbc.2022.101978

Friedman S, Tauber M, Ben-Chaim Y (2020) Sodium ions allosterically modulate the M2 muscarinic receptor. Sci Rep 10:11177. s://doi.org/10.1038/s41598-020-68133-9

Hishinuma S, Kosaka K, Akatsu C, Uesawa Y, Fukui H, Shoji M (2017) Asp73-dependent and -independent regulation of the affinity of ligands for human histamine H1 receptors by Na. Biochem Pharmacol 128:46–54. s://doi.org/10.1016/j.bcp.2016.12.021

Schiffmann A, Gimpl G (2018) Sodium functions as a negative allosteric modulator of the oxytocin receptor. Biochim Biophys Acta Biomembr 1860:1301–1308. s://doi.org/10.1016/j.bbamem.2018.03.003

Koshimizu TA, Kashiwazaki A, Taniguchi J (2016) Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors. Sci Rep 6:25327. s://doi.org/10.1038/srep25327

Ferré G, Gomes AAS, Louet M, Damian M, Bisch PM, Saurel O, Floquet N, Milon A, Banères JL (2023) Sodium is a negative allosteric regulator of the ghrelin receptor. Cell Rep 42:112320. s://doi.org/10.1016/j.celrep.2023.112320

Cong X, Golebiowski J (2018) Allosteric Na+-binding site modulates CXCR4 activation. Phys Chem Chem Phys 20:24915–24920. s://doi.org/10.1039/c8cp04134b

Shihoya W, Nishizawa T, Yamashita K, Inoue A, Hirata K, Kadji FMN, Okuta A, Tani K, Aoki J, Fujiyoshi Y, Doi T, Nureki O (2017) X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog. Nat Struct Mol Biol 24:758–764. s://doi.org/10.1038/nsmb.3450

Hori T, Okuno T, Hirata K, Yamashita K, Kawano Y, Yamamoto M, Hato M, Nakamura M, Shimizu T, Yokomizo T, Miyano M, Yokoyama S (2018) Na+-mimicking ligands stabilize the inactive state of leukotriene B4 receptor BLT1. Nat Chem Biol 14:262–269. https://doi.org/10.1038/nchembio.2547

Luginina A, Gusach A, Marin E, Mishin A, Brouillette R, Popov P, Shiriaeva A, Besserer-Offroy É, Longpré JM, Lyapina E, Ishchenko A, Patel N, Polovinkin V, Safronova N, Bogorodskiy A, Edelweiss E, Hu H, Weierstall U, Liu W, Batyuk A, Gordeliy V, Han GW, Sarret P, Katritch V, Borshchevskiy V, Cherezov V (2019) Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs. Sci Adv 5:eaax2518. https://doi.org/10.1126/sciadv.aax2518

Prasad AS (2013) Discovery of human zinc deficiency: its impact on human health and disease. Adv Nutr 4:176–190. s://doi.org/10.3945/an.112.003210

Cherasse Y, Urade Y (2017) Dietary Zinc Acts as a Sleep Modulator. Int J Mol Sci 18:2334. s://doi.org/10.3390/ijms18112334

Stengaard-Pedersen K, Fredens K, Larsson LI (1981) Inhibition of opiate receptor binding by zinc ions: possible physiological importance in the hippocampus. Peptides 2 Suppl 1:27–35. s://doi.org/10.1016/0196-9781(81)90052-8

Tejwani GA, Hanissian SH (1990) Modulation of mu, delta and kappa opioid receptors in rat brain by metal ions and histidine. Neuropharmacology 29:445–452. https://doi.org/10.1016/0028-3908(90)90166-o

Rodriguez FD, Bardaji E, Traynor JR (1992) Differential effects of Mg2+ and other divalent cations on the binding of tritiated opioid ligands. J Neurochem 59:467–472. s://doi.org/10.1111/j.1471-4159.1992.tb09393.x

Schetz JA, Sibley DR (1997) Zinc allosterically modulates antagonist binding to cloned D1 and D2 dopamine receptors. J Neurochem 68:1990–1997. s://doi.org/10.1046/j.1471-4159.1997.68051990.x

Schetz JA, Chu A, Sibley DR (1999) Zinc modulates antagonist interactions with D2-like dopamine receptors through distinct molecular mechanisms. J Pharmacol Exp Ther 289:956–964.

Schetz JA, Sibley DR (2001) The binding-site crevice of the D4 dopamine receptor is coupled to three distinct sites of allosteric modulation. J Pharmacol Exp Ther 296:359–363.

Swaminath G, Steenhuis J, Kobilka B, Lee TW (2002) Allosteric modulation of beta2-adrenergic receptor by Zn(2+). Mol Pharmacol 61:65–72. s://doi.org/10.1124/mol.61.1.65

Swaminath G, Lee TW, Kobilka B (2003) Identification of an allosteric binding site for Zn2+ on the beta2 adrenergic receptor. J Biol Chem 278:352–356. s://doi.org/10.1074/jbc.M206424200

Ciolek J, Maïga A, Marcon E, Servent D, Gilles N (2011) Pharmacological characterization of zinc and copper interaction with the human alpha(1A)-adrenoceptor. Eur J Pharmacol 655:1–8. s://doi.org/10.1016/j.ejphar.2010.12.042

Oda S, Nishiyama K, Furumoto Y, Yamaguchi Y, Nishimura A, Tang X, Kato Y, Numaga-Tomita T, Kaneko T, Mangmool S, Kuroda T, Okubo R, Sanbo M, Hirabayashi M, Sato Y, Nakagawa Y, Kuwahara K, Nagata R, Iribe G, Mori Y, Nishida M (2022) Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors. Nat Commun 13:6374. s://doi.org/10.1038/s41467-022-34194-9

Holst B, Elling CE, Schwartz TW (2002) Metal ion-mediated agonism and agonist enhancement in melanocortin MC1 and MC4 receptors. J Biol Chem 277:47662–47670. https://doi.org/10.1074/jbc.M202103200

Lagerström MC, Klovins J, Fredriksson R, Fridmanis D, Haitina T, Ling MK, Berglund MM, Schiöth HB (2003) High affinity agonistic metal ion binding sites within the melanocortin 4 receptor illustrate conformational change of transmembrane region 3. J Biol Chem 278:51521–51526. s://doi.org/10.1074/jbc.M307683200

Holst B, Schwartz TW (2003) Molecular mechanism of agonism and inverse agonism in the melanocortin receptors: Zn(2+) as a structural and functional probe. Ann N Y Acad Sci 994:1–11. s://doi.org/10.1111/j.1749-6632.2003.tb03156.x

Park PS, Sapra KT, Koliński M, Filipek S, Palczewski K, Muller DJ (2007) Stabilizing effect of Zn2+ in native bovine rhodopsin. J Biol Chem 282:11377–11385. s://doi.org/10.1074/jbc.M610341200

Barrondo S, Sallés J (2009) Allosteric modulation of 5-HT(1A) receptors by zinc: Binding studies. Neuropharmacology 56:455–462. s://doi.org/10.1016/j.neuropharm.2008.09.018

Satała G, Duszyńska B, Lenda T, Nowak G, Bojarski AJ (2018) Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions. Mol Neurobiol 55:2897–2910. s://doi.org/10.1007/s12035-017-0536-0

Duan J, Shen DD, Zhao T, Guo S, He X, Yin W, Xu P, Ji Y, Chen LN, Liu J, Zhang H, Liu Q, Shi Y, Cheng X, Jiang H, Eric Xu H, Zhang Y, Xie X, Jiang Y (2022) Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors. Nat Commun 13:1364. s://doi.org/10.1038/s41467-022-29072-3

Anderson CT, Radford RJ, Zastrow ML, Zhang DY, Apfel UP, Lippard SJ, Tzounopoulos T (2015) Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc. Proc Natl Acad Sci U S A 112:E2705–E2714. s://doi.org/10.1073/pnas.1503348112

Kalappa BI, Anderson CT, Goldberg JM, Lippard SJ, Tzounopoulos T (2015) AMPA receptor inhibition by synaptically released zinc. Proc Natl Acad Sci U S A 112:15749–15754. s://doi.org/10.1073/pnas.1512296112

Sato S, Huang XP, Kroeze WK, Roth BL (2016) Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc. Mol Pharmacol 90:726–737. https://doi.org/10.1124/mol.116.106112

Starowicz G, Siodłak D, Nowak G, Mlyniec K (2023) The role of GPR39 zinc receptor in the modulation of glutamatergic and GABAergic transmission. Pharmacol Rep 75:609–622. s://doi.org/10.1007/s43440-023-00478-0

Müller A, Kleinau G, Piechowski CL, Müller TD, Finan B, Pratzka J, Grüters A, Krude H, Tschöp M, Biebermann H (2013) G-protein coupled receptor 83 (GPR83) signaling determined by constitutive and zinc(II)-induced activity. PLoS One 8:e53347. s://doi.org/10.1371/journal.pone.0053347

Mack SM, Gomes I, Fakira AK, Duarte ML, Gupta A, Fricker L, Devi LA (2022) GPR83 engages endogenous peptides from two distinct precursors to elicit differential signaling. Mol Pharmacol 102:29–38. s://doi.org/10.1124/molpharm.122.000487

Birnbaumer L, Zurita AR (2010) On the roles of Mg in the activation of G proteins. J Recept Signal Transduct Res 30:372–375. s://doi.org/10.3109/10799893.2010.508165

Williams LT, Mullikin D, Lefkowitz RJ (1978) Magnesium dependence of agonist binding to adenylate cyclase-coupled hormone receptors. J Biol Chem 253:2984–2989.

Pasternak GW, Snowman AM, Snyder SH (1975) Selective enhancement of [3H]opiate agonist binding by divalent cations. Mol Pharmacol 11:735–744.

Sibley DR, Creese I (1983) Regulation of ligand binding to pituitary D-2 dopaminergic receptors. Effects of divalent cations and functional group modification. J Biol Chem 258:4957–4965.

Burgmer U, Schulz U, Tränkle C, Mohr K (1998) Interaction of Mg2+ with the allosteric site of muscarinic M2 receptors. Naunyn Schmiedebergs Arch Pharmacol 357:363–370. s://doi.org/10.1007/pl00005180

Schröter A, Tränkle C, Mohr K (2000) Modes of allosteric interactions with free and [3H]N-methylscopolamine-occupied muscarinic M2 receptors as deduced from buffer-dependent potency shifts. Naunyn Schmiedebergs Arch Pharmacol 362:512–519. s://doi.org/10.1007/s002100000316

Hu X, Provasi D, Ramsey S, Filizola M (2020) Mechanism of μ-Opioid Receptor-Magnesium Interaction and Positive Allosteric Modulation. Biophys J 118:909–921. https://doi.org/10.1016/j.bpj.2019.10.007

Kim J, Jiang Q, Glashofer M, Yehle S, Wess J, Jacobson KA (1996) Glutamate residues in the second extracellular loop of the human A2a adenosine receptor are required for ligand recognition. Mol Pharmacol 49:683–691.

Jiang JY, Nagaraju M, Meyer RC, Zhang L, Hamelberg D, Hall RA, Brown EM, Conn PJ, Yang JJ (2014) Extracellular calcium modulates actions of orthosteric and allosteric ligands on metabotropic glutamate receptor 1α. J Biol Chem 289:1649–1661. https://doi.org/10.1074/jbc.M113.507665

Zou J, Jiang JY, Yang JJ (2017) Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca2. Int J Mol Sci 18:672. https://doi.org/10.3390/ijms18030672

Mazina O, Reinart-Okugbeni R, Kopanchuk S, Rinken A (2012) BacMam system for FRET-based cAMP sensor expression in studies of melanocortin MC1 receptor activation. J Biomol Screen 17:1096–1101. s://doi.org/10.1177/1087057112449862

Yu J, Gimenez LE, Hernandez CC, Wu Y, Wein AH, Han GW, McClary K, Mittal SR, Burdsall K, Stauch B, Wu L, Stevens SN, Peisley A, Williams SY, Chen V, Millhauser GL, Zhao S, Cone RD, Stevens RC (2020) Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding. Science 368:428–433. s://doi.org/10.1126/science.aaz8995

Ma S, Chen Y, Dai A, Yin W, Guo J, Yang D, Zhou F, Jiang Y, Wang MW, Xu HE (2021) Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor. Cell Res 31:1061–1071. s://doi.org/10.1038/s41422-021-00557-y

Eriksen L, Thomsen C (1995) [3H]-L-2-amino-4-phosphonobutyrate labels a metabotropic glutamate receptor, mGluR4a. Br J Pharmacol 116:3279–3287. s://doi.org/10.1111/j.1476-5381.1995.tb15136.x

Kuang D, Hampson DR (2006) Ion dependence of ligand binding to metabotropic glutamate receptors. Biochem Biophys Res Commun 345:1–6. s://doi.org/10.1016/j.bbrc.2006.04.064

Tora AS, Rovira X, Dione I, Bertrand HO, Brabet I, De Koninck Y, Doyon N, Pin JP, Acher F, Goudet C (2015) Allosteric modulation of metabotropic glutamate receptors by chloride ions. FASEB J 29:4174–4188. s://doi.org/10.1096/fj.14-269746

DiRaddo JO, Miller EJ, Bowman-Dalley C, Wroblewska B, Javidnia M, Grajkowska E, Wolfe BB, Liotta DC, Wroblewski JT (2015) Chloride is an Agonist of Group II and III Metabotropic Glutamate Receptors. Mol Pharmacol 88:450–459. s://doi.org/10.1124/mol.114.096420

Tora AS, Rovira X, Cao AM, Cabayé A, Olofsson L, Malhaire F, Scholler P, Baik H, Van Eeckhaut A, Smolders I, Rondard P, Margeat E, Acher F, Pin JP, Goudet C (2018) Chloride ions stabilize the glutamate-induced active state of the metabotropic glutamate receptor 3. Neuropharmacology 140:275–286. s://doi.org/10.1016/j.neuropharm.2018.08.011

Liu H, Yi P, Zhao W, Wu Y, Acher F, Pin JP, Liu J, Rondard P (2020) Illuminating the allosteric modulation of the calcium-sensing receptor. Proc Natl Acad Sci U S A 117:21711–21722. s://doi.org/10.1073/pnas.1922231117

Nuemket N, Yasui N, Kusakabe Y, Nomura Y, Atsumi N, Akiyama S, Nango E, Kato Y, Kaneko MK, Takagi J, Hosotani M, Yamashita A (2017) Structural basis for perception of diverse chemical substances by T1r taste receptors. Nat Commun 8:15530. https://doi.org/10.1038/ncomms15530

Atsumi N, Yasumatsu K, Takashina Y, Ito C, Yasui N, Margolskee RF, Yamashita A (2023) Chloride ions evoke taste sensations by binding to the extracellular ligand-binding domain of sweet/umami taste receptors. Elife 12:e84291. s://doi.org/10.7554/eLife.84291

Mitchell DC, Niu SL, Litman BJ (2001) Optimization of receptor-G protein coupling by bilayer lipid composition I: kinetics of rhodopsin-transducin binding. J Biol Chem 276:42801–42806. s://doi.org/10.1074/jbc.M105772200

Soubias O, Teague WE Jr, Hines KG, Mitchell DC, Gawrisch K (2010) Contribution of membrane elastic energy to rhodopsin function. Biophys J 99:817–824. s://doi.org/10.1016/j.bpj.2010.04.068

Soubias O, Gawrisch K (2012) The role of the lipid matrix for structure and function of the GPCR rhodopsin. Biochim Biophys Acta 1818:234–240. s://doi.org/10.1016/j.bbamem.2011.08.034

Soubias O, Sodt AJ, Teague WE, Hines KG, Gawrisch K (2023) Physiological changes in bilayer thickness induced by cholesterol control GPCR rhodopsin function. Biophys J 122:973–983. s://doi.org/10.1016/j.bpj.2022.11.2937

Kubatova N, Schmidt T, Schwieters CD, Clore GM (2023) Quantitative analysis of sterol-modulated monomer-dimer equilibrium of the β1-adrenergic receptor by DEER spectroscopy. Proc Natl Acad Sci U S A 120:e2221036120. s://doi.org/10.1073/pnas.2221036120

Poudel B, Rajeshwar T R, Vanegas JM (2023) Membrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor. Nat Commun 14:4690. s://doi.org/10.1038/s41467-023-40433-4

Ray AP, Thakur N, Pour NG, Eddy MT (2023) Dual mechanisms of cholesterol-GPCR interactions that depend on membrane phospholipid composition. Structure 31:836-847.e6. s://doi.org/10.1016/j.str.2023.05.001

Ostrom RS, Insel PA (2004) The evolving role of lipid rafts and caveolae in G protein-coupled receptor signaling: implications for molecular pharmacology. Br J Pharmacol 143:235–245. s://doi.org/10.1038/sj.bjp.0705930

Patel HH, Murray F, Insel PA (2008) G-protein-coupled receptor-signaling components in membrane raft and caveolae microdomains. Handb Exp Pharmacol (186):167–184. s://doi.org/10.1007/978-3-540-72843-6_7

Kunselman JM, Lott J, Puthenveedu MA (2021) Mechanisms of selective G protein-coupled receptor localization and trafficking. Curr Opin Cell Biol 71:158–165. s://doi.org/10.1016/j.ceb.2021.03.002

Kimura T, Ohta T, Watanabe K, Yoshimura H, Yamamoto I (1998) Anandamide, an endogenous cannabinoid receptor ligand, also interacts with 5-hydroxytryptamine (5-HT) receptor. Biol Pharm Bull 21:22422–22426. s://doi.org/10.1248/bpb.21.224

Christopoulos A, Wilson K (2001) Interaction of anandamide with the M(1) and M(4) muscarinic acetylcholine receptors. Brain Res 915:70–78. s://doi.org/10.1016/s0006-8993(01)02825-6

Lanzafame AA, Guida E, Christopoulos A (2004) Effects of anandamide on the binding and signaling properties of M1 muscarinic acetylcholine receptors. Biochem Pharmacol 68:2207–2219. s://doi.org/10.1016/j.bcp.2004.08.005

Lane JR, Beukers MW, Mulder-Krieger T, Ijzerman AP (2010) The endocannabinoid 2-arachidonylglycerol is a negative allosteric modulator of the human A3 adenosine receptor. Biochem Pharmacol 79:48–56. s://doi.org/10.1016/j.bcp.2009.07.024

Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y (2012) Endocannabinoid signaling and synaptic function. Neuron 76:70–81. s://doi.org/10.1016/j.neuron.2012.09.020

Pamplona FA, Ferreira J, Menezes de Lima O Jr, Duarte FS, Bento AF, Forner S, Villarinho JG, Bellocchio L, Wotjak CT, Lerner R, Monory K, Lutz B, Canetti C, Matias I, Calixto JB, Marsicano G, Guimarães MZ, Takahashi RN (2012) Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proc Natl Acad Sci U S A 109:21134–21139. s://doi.org/10.1073/pnas.1202906109

Pertwee RG (2012) Lipoxin A4 is an allosteric endocannabinoid that strengthens anandamide-induced CB1 receptor activation. Proc Natl Acad Sci U S A 109:20781–20782. s://doi.org/10.1073/pnas.1218529110

Khurana L, Mackie K, Piomelli D, Kendall DA (2017) Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities. Neuropharmacology 124:3–12. s://doi.org/10.1016/j.neuropharm.2017.05.018

Thomas EA, Carson MJ, Sutcliffe JG (1998) Oleamide-induced modulation of 5-hydroxytryptamine receptor-mediated signaling. Ann N Y Acad Sci 861:183–189. s://doi.org/10.1111/j.1749-6632.1998.tb10190.x

Hedlund PB, Carson MJ, Sutcliffe JG, Thomas EA (1999) Allosteric regulation by oleamide of the binding properties of 5-hydroxytryptamine7 receptors. Biochem Pharmacol 58:1807–1813. s://doi.org/10.1016/s0006-2952(99)00274-9

Hiley CR, Hoi PM (2007) Oleamide: a fatty acid amide signaling molecule in the cardiovascular system? Cardiovasc Drug Rev 25:46–60. s://doi.org/10.1111/j.1527-3466.2007.00004.x

Grazzini E, Guillon G, Mouillac B, Zingg HH (1998) Inhibition of oxytocin receptor function by direct binding of progesterone. Nature 392:509–512. s://doi.org/10.1038/33176

Yallampalli C, Kondapaka SB, Lanlua P, Wimalawansa SJ, Gangula PR (2004) Female sex steroid hormones and pregnancy regulate receptors for calcitonin gene-related peptide in rat mesenteric arteries, but not in aorta. Biol Reprod 70:1055–1062. s://doi.org/10.1095/biolreprod.103.022467

Rossi M, Dimida A, Ferrarini E, Silvano E, De Marco G, Agretti P, Aloisi G, Simoncini T, Di Bari L, Tonacchera M, Giorgi F, Maggio R (2009) Presence of a putative steroidal allosteric site on glycoprotein hormone receptors. Eur J Pharmacol 623:155–159. s://doi.org/10.1016/j.ejphar.2009.09.029

Vallée M, Vitiello S, Bellocchio L, Hébert-Chatelain E, Monlezun S, Martin-Garcia E, Kasanetz F, Baillie GL, Panin F, Cathala A, Roullot-Lacarrière V, Fabre S, Hurst DP, Lynch DL, Shore DM, Deroche-Gamonet V, Spampinato U, Revest JM, Maldonado R, Reggio PH, Ross RA, Marsicano G, Piazza PV (2014) Pregnenolone can protect the brain from cannabis intoxication. Science 343:94–98. s://doi.org/10.1126/science.1243985

Busquets-Garcia A, Soria-Gómez E, Redon B, Mackenbach Y, Vallée M, Chaouloff F, Varilh M, Ferreira G, Piazza PV, Marsicano G (2017) Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice. Mol Psychiatry 22:1594–1603. https://doi.org/10.1038/mp.2017.4

Kolatorova L, Vitku J, Suchopar J, Hill M, Parizek A (2022) Progesterone: A Steroid with Wide Range of Effects in Physiology as Well as Human Medicine. Int J Mol Sci 23:7989. s://doi.org/10.3390/ijms23147989

Paila YD, Kombrabail M, Krishnamoorthy G, Chattopadhyay A (2011) Oligomerization of the serotonin(1A) receptor in live cells: a time-resolved fluorescence anisotropy approach. J Phys Chem B 115:11439–11447. s://doi.org/10.1021/jp201458h

Sejdiu BI, Tieleman DP (2020) Lipid-Protein Interactions Are a Unique Property and Defining Feature of G Protein-Coupled Receptors. Biophys J 118:1887–1900. https://doi.org/10.1016/j.bpj.2020.03.008

Janetzko J, Kise R, Barsi-Rhyne B, Siepe DH, Heydenreich FM, Kawakami K, Masureel M, Maeda S, Garcia KC, von Zastrow M, Inoue A, Kobilka BK (2022) Membrane phosphoinositides regulate GPCR-β-arrestin complex assembly and dynamics. Cell 185:4560-4573.e19. s://doi.org/10.1016/j.cell.2022.10.018

Tzortzini E, Kolocouris A (2023) Molecular Biophysics of Class A G Protein Coupled Receptors-Lipids Interactome at a Glance-Highlights from the A2A Adenosine Receptor. Biomolecules 13:957. s://doi.org/10.3390/biom13060957

Fantini J, Barrantes FJ (2013) How cholesterol interacts with membrane proteins: an exploration of cholesterol-binding sites including CRAC, CARC, and tilted domains. Front Physiol 4:31. s://doi.org/10.3389/fphys.2013.00031

Krishna Kumar K, Shalev-Benami M, Robertson MJ, Hu H, Banister SD, Hollingsworth SA, Latorraca NR, Kato HE, Hilger D, Maeda S, Weis WI, Farrens DL, Dror RO, Malhotra SV, Kobilka BK, Skiniotis G (2019) Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell 176:448-458.e12. s://doi.org/10.1016/j.cell.2018.11.040

Xing C, Zhuang Y, Xu TH, Feng Z, Zhou XE, Chen M, Wang L, Meng X, Xue Y, Wang J, Liu H, McGuire TF, Zhao G, Melcher K, Zhang C, Xu HE, Xie XQ (2020) Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex. Cell 180:645-654.e13. s://doi.org/10.1016/j.cell.2020.01.007

Gimpl G, Burger K, Fahrenholz F (1997) Cholesterol as modulator of receptor function. Biochemistry 36:10959–10974. s://doi.org/10.1021/bi963138w

Eroglu C, Brugger B, Wieland F, Sinning I (2003) Glutamate-binding affinity of Drosophila metabotropic glutamate receptor is modulated by association with lipid rafts. Proc Natl Acad Sci U S A 100:10219–10224. s://doi.org/10.1073/pnas.1737042100

Prasad R, Paila YD, Chattopadhyay A (2009) Membrane cholesterol depletion enhances ligand binding function of human serotonin1A receptors in neuronal cells. Biochem Biophys Res Commun 390:93–96. s://doi.org/10.1016/j.bbrc.2009.09.072

Potter RM, Harikumar KG, Wu SV, Miller LJ (2012) Differential sensitivity of types 1 and 2 cholecystokinin receptors to membrane cholesterol. J Lipid Res 53:137–148. https://doi.org/10.1194/jlr.M020065

Navratil AM, Bliss SP, Berghorn KA, Haughian JM, Farmerie TA, Graham JK, Clay CM, Roberson MS (2003) Constitutive localization of the gonadotropin-releasing hormone (GnRH) receptor to low density membrane microdomains is necessary for GnRH signaling to ERK. J Biol Chem 278:31593–31602. s://doi.org/10.1074/jbc.M304273200

Levitt ES, Clark MJ, Jenkins PM, Martens JR, Traynor JR (2009) Differential effect of membrane cholesterol removal on mu- and delta-opioid receptors: a parallel comparison of acute and chronic signaling to adenylyl cyclase. J Biol Chem 284:22108–22122. s://doi.org/10.1074/jbc.M109.030411

Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola VP, Chien EY, Velasquez J, Kuhn P, Stevens RC (2008) A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure 16:897–905. s://doi.org/10.1016/j.str.2008.05.001

Jafurulla M, Tiwari S, Chattopadhyay A (2011) Identification of cholesterol recognition amino acid consensus (CRAC) motif in G-protein coupled receptors. Biochem Biophys Res Commun 404:569–573. s://doi.org/10.1016/j.bbrc.2010.12.031

Thal DM, Sun B, Feng D, Nawaratne V, Leach K, Felder CC, Bures MG, Evans DA, Weis WI, Bachhawat P, Kobilka TS, Sexton PM, Kobilka BK, Christopoulos A (2016) Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature 531:335–340. s://doi.org/10.1038/nature17188

Maeda S, Xu J, N Kadji FM, Clark MJ, Zhao J, Tsutsumi N, Aoki J, Sunahara RK, Inoue A, Garcia KC, Kobilka BK (2020) Structure and selectivity engineering of the M1 muscarinic receptor toxin complex. Science 369:161–167. s://doi.org/10.1126/science.aax2517

Randáková A, Dolejší E, Rudajev V, Zimčík P, Doležal V, El-Fakahany EE, Jakubík J (2018) Role of membrane cholesterol in differential sensitivity of muscarinic receptor subtypes to persistently bound xanomeline. Neuropharmacology 133:129–144. https://doi.org/10.1016/j.neuropharm.2018.01.027

Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC (2012) Structure of the human κ-opioid receptor in complex with JDTic. Nature 485(7398):327–332. s://doi.org/10.1038/nature10939

Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, Lansu K, Schools ZL, Che T, Nichols DE, Shoichet BK, Dror RO, Roth BL (2017) Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell 168:377-389.e12. https://doi.org/10.1016/j.cell.2016.12.033

McCorvy JD, Wacker D, Wang S, Agegnehu B, Liu J, Lansu K, Tribo AR, Olsen RHJ, Che T, Jin J, Roth BL (2018) Structural determinants of 5-HT2B receptor activation and biased agonism. Nat Struct Mol Biol 25:787–796. s://doi.org/10.1038/s41594-018-0116-7

Wingler LM, Skiba MA, McMahon C, Staus DP, Kleinhenz ALW, Suomivuori CM, Latorraca NR, Dror RO, Lefkowitz RJ, Kruse AC (2020) Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR. Science 367:888–892. https://doi.org/10.1126/science.aay9813

Segala E, Guo D, Cheng RK, Bortolato A, Deflorian F, Doré AS, Errey JC, Heitman LH, IJzerman AP, Marshall FH, Cooke RM (2016) Controlling the Dissociation of Ligands from the Adenosine A2A Receptor through Modulation of Salt Bridge Strength. J Med Chem 59:6470–6479. s://doi.org/10.1021/acs.jmedchem.6b00653

Che T, English J, Krumm BE, Kim K, Pardon E, Olsen RHJ, Wang S, Zhang S, Diberto JF, Sciaky N, Carroll FI, Steyaert J, Wacker D, Roth BL (2020) Nanobody-enabled monitoring of kappa opioid receptor states. Nat Commun 11:1145. s://doi.org/10.1038/s41467-020-14889-7

Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S (2012) Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. Nature 485:321–326. s://doi.org/10.1038/nature10954

Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, Kato HE, Livingston KE, Thorsen TS, Kling RC, Granier S, Gmeiner P, Husbands SM, Traynor JR, Weis WI, Steyaert J, Dror RO, Kobilka BK (2015) Structural insights into µ-opioid receptor activation. Nature 524:315–321. s://doi.org/10.1038/nature14886

Zhang K, Zhang J, Gao ZG, Zhang D, Zhu L, Han GW, Moss SM, Paoletta S, Kiselev E, Lu W, Fenalti G, Zhang W, Müller CE, Yang H, Jiang H, Cherezov V, Katritch V, Jacobson KA, Stevens RC, Wu B, Zhao Q (2014) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature 509:115–118. s://doi.org/10.1038/nature13083

Liu K, Wu L, Yuan S, Wu M, Xu Y, Sun Q, Li S, Zhao S, Hua T, Liu ZJ (2020) Structural basis of CXC chemokine receptor 2 activation and signalling. Nature 585:135–140. s://doi.org/10.1038/s41586-020-2492-5

Zhuang Y, Liu H, Edward Zhou X, Kumar Verma R, de Waal PW, Jang W, Xu TH, Wang L, Meng X, Zhao G, Kang Y, Melcher K, Fan H, Lambert NA, Eric Xu H, Zhang C (2020) Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling. Nat Commun 11:885. s://doi.org/10.1038/s41467-020-14728-9

Claff T, Yu J, Blais V, Patel N, Martin C, Wu L, Han GW, Holleran BJ, Van der Poorten O, White KL, Hanson MA, Sarret P, Gendron L, Cherezov V, Katritch V, Ballet S, Liu ZJ, Müller CE, Stevens RC (2019) Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists. Sci Adv 5:eaax9115. s://doi.org/10.1126/sciadv.aax9115

Miles TF, Spiess K, Jude KM, Tsutsumi N, Burg JS, Ingram JR, Waghray D, Hjorto GM, Larsen O, Ploegh HL, Rosenkilde MM, Garcia KC (2018) Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy. Elife 7:e35850. s://doi.org/10.7554/eLife.35850

Waltenspühl Y, Schöppe J, Ehrenmann J, Kummer L, Plückthun A (2020) Crystal structure of the human oxytocin receptor. Sci Adv 6:eabb5419. s://doi.org/10.1126/sciadv.abb5419

Gusach A, Luginina A, Marin E, Brouillette RL, Besserer-Offroy É, Longpré JM, Ishchenko A, Popov P, Patel N, Fujimoto T, Maruyama T, Stauch B, Ergasheva M, Romanovskaia D, Stepko A, Kovalev K, Shevtsov M, Gordeliy V, Han GW, Katritch V, Borshchevskiy V, Sarret P, Mishin A, Cherezov V (2019) Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors. Nat Commun 10:5573. https://doi.org/10.1038/s41467-019-13348-2

Chen T, Xiong M, Zong X, Ge Y, Zhang H, Wang M, Won Han G, Yi C, Ma L, Ye RD, Xu Y, Zhao Q, Wu B (2020) Structural basis of ligand binding modes at the human formyl peptide receptor 2. Nat Commun 11:1208. s://doi.org/10.1038/s41467-020-15009-1

Babcock GJ, Farzan M, Sodroski J (2003) Ligand-independent dimerization of CXCR4, a principal HIV-1 coreceptor. J Biol Chem 278:3378–3385. s://doi.org/10.1074/jbc.M210140200

Calmet P, Cullin C, Cortès S, Vang M, Caudy N, Baccouch R, Dessolin J, Maamar NT, Lecomte S, Tillier B, Alves ID (2020) Cholesterol impacts chemokine CCR5 receptor ligand-binding activity. FEBS J 287:2367–2385. s://doi.org/10.1111/febs.15145

Ruthirakuhan M, Herrmann N, Andreazza AC, Verhoeff NPLG, Gallagher D, Black SE, Kiss A, Lanctôt KL (2019) 24S-Hydroxycholesterol Is Associated with Agitation Severity in Patients with Moderate-to-Severe Alzheimer's Disease: Analyses from a Clinical Trial with Nabilone. J Alzheimers Dis 71:21–31. s://doi.org/10.3233/JAD-190202

Guixà-González R, Albasanz JL, Rodriguez-Espigares I, Pastor M, Sanz F, Martí-Solano M, Manna M, Martinez-Seara H, Hildebrand PW, Martín M, Selent J (2017) Membrane cholesterol access into a G-protein-coupled receptor. Nat Commun 8:14505. s://doi.org/10.1038/ncomms14505

McGraw C, Yang L, Levental I, Lyman E, Robinson AS (2019) Membrane cholesterol depletion reduces downstream signaling activity of the adenosine A2A receptor. Biochim Biophys Acta Biomembr 1861:760–767. s://doi.org/10.1016/j.bbamem.2019.01.001

Szczurowska E, Szánti-Pintér E, Randáková A, Jakubík J, Kudova E (2022) Allosteric Modulation of Muscarinic Receptors by Cholesterol, Neurosteroids and Neuroactive Steroids. Int J Mol Sci 23:13075. s://doi.org/10.3390/ijms232113075

Michal P, Rudajev V, El-Fakahany EE, Dolezal V (2009) Membrane cholesterol content influences binding properties of muscarinic M2 receptors and differentially impacts activation of second messenger pathways. Eur J Pharmacol 606:50–60. s://doi.org/10.1016/j.ejphar.2009.01.028

Michal P, El-Fakahany EE, Doležal V (2015) Changes in Membrane Cholesterol Differentially Influence Preferential and Non-preferential Signaling of the M1 and M3 Muscarinic Acetylcholine Receptors. Neurochem Res 40:2068–2077. s://doi.org/10.1007/s11064-014-1325-z

Jakubik J, El-Fakahany EE (2020) Current Advances in Allosteric Modulation of Muscarinic Receptors. Biomolecules 10:325. s://doi.org/10.3390/biom10020325

Oates J, Watts A (2011) Uncovering the intimate relationship between lipids, cholesterol and GPCR activation. Curr Opin Struct Biol 21:802–807. s://doi.org/10.1016/j.sbi.2011.09.007

Geiger J, Sexton R, Al-Sahouri Z, Lee MY, Chun E, Harikumar KG, Miller LJ, Beckstein O, Liu W (2021) Evidence that specific interactions play a role in the cholesterol sensitivity of G protein-coupled receptors. Biochim Biophys Acta Biomembr 1863:183557. s://doi.org/10.1016/j.bbamem.2021.183557

Prasanna X, Chattopadhyay A, Sengupta D (2014) Cholesterol modulates the dimer interface of the β₂-adrenergic receptor via cholesterol occupancy sites. Biophys J 106:1290–1300. s://doi.org/10.1016/j.bpj.2014.02.002

Dainese E, Oddi S, Maccarrone M (2008) Lipid-mediated dimerization of beta2-adrenergic receptor reveals important clues for cannabinoid receptors. Cell Mol Life Sci 65:2277–2279. s://doi.org/10.1007/s00018-008-8139-6

Wang J, He L, Combs CA, Roderiquez G, Norcross MA (2006) Dimerization of CXCR4 in living malignant cells: control of cell migration by a synthetic peptide that reduces homologous CXCR4 interactions. Mol Cancer Ther 5:2474–2483. s://doi.org/10.1158/1535-7163.MCT-05-0261

Ganguly S, Clayton AH, Chattopadhyay A (2011) Organization of higher-order oligomers of the serotonin₁(A) receptor explored utilizing homo-FRET in live cells. Biophys J 100:361–368. s://doi.org/10.1016/j.bpj.2010.12.3692

Sarkar P, Mozumder S, Bej A, Mukherjee S, Sengupta J, Chattopadhyay A (2020) Structure, dynamics and lipid interactions of serotonin receptors: excitements and challenges. Biophys Rev 13:101–122. s://doi.org/10.1007/s12551-020-00772-8

Mahesh G, Jaiswal P, Dey S, Sengupta J, Mukherjee S (2018) Cloning, Expression, Purification and Characterization of Oligomeric States of the Native 5HT2A G-Protein-Coupled Receptor. Protein Pept Lett 25:390–397. s://doi.org/10.2174/0929866525666180207110137

Massaccesi L, Laudadio E, Mobbili G, Minnelli C, Galeazzi R (2020) Cholesterol-mediated oligomerization pathways of serotonin G-coupled receptor 5-HT2C. Int J Biol Macromol 160:1090–1100. s://doi.org/10.1016/j.ijbiomac.2020.05.231

Liste MJ, Caltabiano G, Ward RJ, Alvarez-Curto E, Marsango S, Milligan G (2015) The molecular basis of oligomeric organization of the human M3 muscarinic acetylcholine receptor. Mol Pharmacol 87:936–953. s://doi.org/10.1124/mol.114.096925

Milligan G, Ward RJ, Marsango S (2019) GPCR homo-oligomerization. Curr Opin Cell Biol 57:40–47. s://doi.org/10.1016/j.ceb.2018.10.007

Isu UH, Badiee SA, Khodadadi E, Moradi M (2023) Cholesterol in Class C GPCRs: Role, Relevance, and Localization. Membranes (Basel) 13:301. s://doi.org/10.3390/membranes13030301

Park J, Zuo H, Frangaj A, Fu Z, Yen LY, Zhang Z, Mosyak L, Slavkovich VN, Liu J, Ray KM, Cao B, Vallese F, Geng Y, Chen S, Grassucci R, Dandey VP, Tan YZ, Eng E, Lee Y, Kloss B, Liu Z, Hendrickson WA, Potter CS, Carragher B, Graziano J, Conigrave AD, Frank J, Clarke OB, Fan QR (2021) Symmetric activation and modulation of the human calcium-sensing receptor. Proc Natl Acad Sci U S A 118:e2115849118. s://doi.org/10.1073/pnas.2115849118

Patil DN, Singh S, Laboute T, Strutzenberg TS, Qiu X, Wu D, Novick SJ, Robinson CV, Griffin PR, Hunt JF, Izard T, Singh AK, Martemyanov KA (2022) Cryo-EM structure of human GPR158 receptor coupled to the RGS7-Gβ5 signaling complex. Science 375:86–91. s://doi.org/10.1126/science.abl4732

Kim Y, Jeong E, Jeong JH, Kim Y, Cho Y (2020) Structural Basis for Activation of the Heterodimeric GABAB Receptor. J Mol Biol 432:5966–5984. s://doi.org/10.1016/j.jmb.2020.09.023

Moreau CJ, Audic G, Lemel L, García-Fernández MD, Nieścierowicz K (2023) Interactions of cholesterol molecules with GPCRs in different states: A comparative analysis of GPCRs' structures. Biochim Biophys Acta Biomembr 1865:184100. s://doi.org/10.1016/j.bbamem.2022.184100

Vance JE (2012) Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis Model Mech 5:746–755. s://doi.org/10.1242/dmm.010124

Ridker PM (2014) LDL cholesterol: controversies and future therapeutic directions. Lancet 384:607–617. s://doi.org/10.1016/S0140-6736(14)61009-6

Baccouch R, Rascol E, Stoklosa K, Alves ID (2022) The role of the lipid environment in the activity of G protein coupled receptors. Biophys Chem 285:106794. s://doi.org/10.1016/j.bpc.2022.106794

Eichel K, Jullié D, Barsi-Rhyne B, Latorraca NR, Masureel M, Sibarita JB, Dror RO, von Zastrow M (2018) Catalytic activation of β-arrestin by GPCRs. Nature 557:381–386. https://doi.org/10.1038/s41586-018-0079-1

Gaidarov I, Krupnick JG, Falck JR, Benovic JL, Keen JH (1999) Arrestin function in G protein-coupled receptor endocytosis requires phosphoinositide binding. EMBO J 18:871–881. s://doi.org/10.1093/emboj/18.4.871

Kadlecova Z, Spielman SJ, Loerke D, Mohanakrishnan A, Reed DK, Schmid SL (2017) Regulation of clathrin-mediated endocytosis by hierarchical allosteric activation of AP2. J Cell Biol 216:167–179. s://doi.org/10.1083/jcb.201608071

Huang W, Masureel M, Qu Q, Janetzko J, Inoue A, Kato HE, Robertson MJ, Nguyen KC, Glenn JS, Skiniotis G, Kobilka BK (2020) Structure of the neurotensin receptor 1 in complex with β-arrestin 1. Nature 579:303–308. s://doi.org/10.1038/s41586-020-1953-1

Song W, Yen HY, Robinson CV, Sansom MSP (2019) State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes. Structure 27:392-403.e3. https://doi.org/10.1016/j.str.2018.10.024

White AD, Jean-Alphonse FG, Fang F, Peña KA, Liu S, König GM, Inoue A, Aslanoglou D, Gellman SH, Kostenis E, Xiao K, Vilardaga JP (2020) Gq/11-dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR. Proc Natl Acad Sci U S A 117:7455–7460. s://doi.org/10.1073/pnas.1918158117

Ehrenmann J, Schöppe J, Klenk C, Rappas M, Kummer L, Doré AS, Plückthun A (2018) High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist. Nat Struct Mol Biol 25:1086–1092. s://doi.org/10.1038/s41594-018-0151-4

Zhao LH, Ma S, Sutkeviciute I, Shen DD, Zhou XE, de Waal PW, Li CY, Kang Y, Clark LJ, Jean-Alphonse FG, White AD, Yang D, Dai A, Cai X, Chen J, Li C, Jiang Y, Watanabe T, Gardella TJ, Melcher K, Wang MW, Vilardaga JP, Xu HE, Zhang Y (2019) Structure and dynamics of the active human parathyroid hormone receptor-1. Science 364:148–153. s://doi.org/10.1126/science.aav7942

Sutkeviciute I, Vilardaga JP (2020) Structural insights into emergent signaling modes of G protein-coupled receptors. J Biol Chem 295:11626–11642. s://doi.org/10.1074/jbc.REV120.009348

Conigrave AD, Quinn SJ, Brown EM (2000) L-amino acid sensing by the extracellular Ca2+-sensing receptor. Proc Natl Acad Sci U S A 97:4814–4819. s://doi.org/10.1073/pnas.97.9.4814

Mun HC, Culverston EL, Franks AH, Collyer CA, Clifton-Bligh RJ, Conigrave AD (2005) A double mutation in the extracellular Ca2+-sensing receptor's venus flytrap domain that selectively disables L-amino acid sensing. J Biol Chem 280:29067–29072. s://doi.org/10.1074/jbc.M500002200

Lee HJ, Mun HC, Lewis NC, Crouch MF, Culverston EL, Mason RS, Conigrave AD (2007) Allosteric activation of the extracellular Ca2+-sensing receptor by L-amino acids enhances ERK1/2 phosphorylation. Biochem J 404:141–149. s://doi.org/10.1042/BJ20061826

Davey AE, Leach K, Valant C, Conigrave AD, Sexton PM, Christopoulos A (2012) Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor. Endocrinology 153:1232–1241. s://doi.org/10.1210/en.2011-1426

Kerr DI, Ong J (2003) Potentiation of metabotropic GABAB receptors by L-amino acids and dipeptides in rat neocortex. Eur J Pharmacol 468:103–108. s://doi.org/10.1016/s0014-2999(03)01675-3

Urwyler S, Gjoni T, Kaupmann K, Pozza MF, Mosbacher J (2004) Selected amino acids, dipeptides and arylalkylamine derivatives do not act as allosteric modulators at GABAB receptors. Eur J Pharmacol 483:147–153. s://doi.org/10.1016/j.ejphar.2003.10.024

Agnati LF, Ferré S, Genedani S, Leo G, Guidolin D, Filaferro M, Carriba P, Casadó V, Lluis C, Franco R, Woods AS, Fuxe K (2006) Allosteric modulation of dopamine D2 receptors by homocysteine. J Proteome Res 5:3077–3083. s://doi.org/10.1021/pr0601382

Hu XW, Qin SM, Li D, Hu LF, Liu CF (2013) Elevated homocysteine levels in levodopa-treated idiopathic Parkinson's disease: a meta-analysis. Acta Neurol Scand 128:73–82. s://doi.org/10.1111/ane.12106

Fasciani I, Petragnano F, Aloisi G, Marampon F, Carli M, Scarselli M, Maggio R, Rossi M (2020 Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics. Pharmaceuticals (Basel) 13:388. s://doi.org/10.3390/ph13110388

Molderings GJ, Menzel S, Kathmann M, Schlicker E, Göthert M (2000) Dual interaction of agmatine with the rat alpha(2D)-adrenoceptor: competitive antagonism and allosteric activation. Br J Pharmacol 130:1706-1712. s://doi.org/10.1038/sj.bjp.0703495

Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH, Haenisch B, Halaris A, Hong S, Lee JE, Li J, Liu P, Molderings GJ, Rodrigues AL, Satriano J, Seong GJ, Wilcox G, Wu N, Gilad GM (2013) Agmatine: clinical applications after 100 years in translation. Drug Discov Today 18:880–893. s://doi.org/10.1016/j.drudis.2013.05.017

Maltsev AV (2018) Agmatine modulates calcium handling in cardiomyocytes of hibernating ground squirrels through calcium-sensing receptor signaling. Cell Signal 51:1–12. s://doi.org/10.1016/j.cellsig.2018.07.004

Shin S, Awuah Boadi E, Shah S, Ezell M, Li P, Bandyopadhyay BC (2023) Anti-inflammatory role of extracellular l-arginine through calcium sensing receptor in human renal proximal tubular epithelial (HK-2) cells. Int Immunopharmacol 117:109853. s://doi.org/10.1016/j.intimp.2023.109853

Massot O, Rousselle JC, Fillion MP, Grimaldi B, Cloëz-Tayarani I, Fugelli A, Prudhomme N, Seguin L, Rousseau B, Plantefol M, Hen R, Fillion G (1996) 5-hydroxytryptamine-moduline, a new endogenous cerebral peptide, controls the serotonergic activity via its specific interaction with 5-hydroxytryptamine1B/1D receptors. Mol Pharmacol 50:752–762.

Massot O, Rousselle JC, Grimaldi B, Cloëz-Tayarani I, Fillion MP, Plantefol M, Bonnin A, Prudhomme N, Fillion G (1998) Molecular, cellular and physiological characteristics of 5-HT-moduline, a novel endogenous modulator of 5-HT1B receptor subtype. Ann N Y Acad Sci 861:174–182. s://doi.org/10.1111/j.1749-6632.1998.tb10189.x

Fillion G (2000) Potential of 5-HT-moduline as a drug target for affective disorders. Curr Opin Investig Drugs 1:104-109.

Bonnin A, Grimaldi B, Fillion MP, Fillion G (1999) Acute stress induces a differential increase of 5-HT-moduline (LSAL) tissue content in various rat brain areas. Brain Res 825:152–160. s://doi.org/10.1016/s0006-8993(99)01265-2

Gomes I, Grushko JS, Golebiewska U, Hoogendoorn S, Gupta A, Heimann AS, Ferro ES, Scarlata S, Fricker LD, Devi LA (2009) Novel endogenous peptide agonists of cannabinoid receptors. FASEB J 23:3020–3029. s://doi.org/10.1096/fj.09-132142

Bauer M, Chicca A, Tamborrini M, Eisen D, Lerner R, Lutz B, Poetz O, Pluschke G, Gertsch J (2012) Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors. J Biol Chem 287:36944–36967. s://doi.org/10.1074/jbc.M112.382481

Petrucci V, Chicca A, Glasmacher S, Paloczi J, Cao Z, Pacher P, Gertsch J (2017) Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage. Sci Rep 7:9560. https://doi.org/10.1038/s41598-017-09808-8

Straiker A, Mitjavila J, Yin D, Gibson A, Mackie K (2015) Aiming for allosterism: Evaluation of allosteric modulators of CB1 in a neuronal model. Pharmacol Res 99:370–376. s://doi.org/10.1016/j.phrs.2015.07.017

Heimann AS, Gomes I, Dale CS, Pagano RL, Gupta A, de Souza LL, Luchessi AD, Castro LM, Giorgi R, Rioli V, Ferro ES, Devi LA (2007) Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc Natl Acad Sci U S A 104:20588–20593. https://doi.org/10.1073/pnas.0706980105

de Kloet AD, Woods SC (2009) Minireview: Endocannabinoids and their receptors as targets for obesity therapy. Endocrinology 150:2531–2536. s://doi.org/10.1210/en.2009-0046

Macedonio G, Stefanucci A, Maccallini C, Mirzaie S, Novellino E, Mollica A (2016) Hemopressin Peptides as Modulators of the Endocannabinoid System and their Potential Applications as Therapeutic Tools. Protein Pept Lett 23:1045–1051. s://doi.org/10.2174/0929866523666161007152435

Glasmacher S, Gertsch J (2021) Characterization of pepcan-23 as pro-peptide of RVD-hemopressin (pepcan-12) and stability of hemopressins in mice. Adv Biol Regul 80:100808. s://doi.org/10.1016/j.jbior.2021.100808

Han ZL, Fang Q, Wang ZL, Li XH, Li N, Chang XM, Pan JX, Tang HZ, Wang R (2014) Antinociceptive effects of central administration of the endogenous cannabinoid receptor type 1 agonist VDPVNFKLLSH-OH [(m)VD-hemopressin(α)], an N-terminally extended hemopressin peptide. J Pharmacol Exp Ther 348:316–323. s://doi.org/10.1124/jpet.113.209866

Zheng T, Zhang T, Zhang R, Wang ZL, Han ZL, Li N, Li XH, Zhang MN, Xu B, Yang XL, Fang Q, Wang R (2017) Pharmacological characterization of rat VD-hemopressin(α), an α-hemoglobin-derived peptide exhibiting cannabinoid agonist-like effects in mice. Neuropeptides 63:83–90. s://doi.org/10.1016/j.npep.2016.12.006

Yuan J, Jiang C, Wang J, Chen CJ, Hao Y, Zhao G, Feng Z, Xie XQ (2022) In Silico Prediction and Validation of CB2 Allosteric Binding Sites to Aid the Design of Allosteric Modulators. Molecules 27:453. s://doi.org/10.3390/molecules27020453

Raphael-Mizrahi B, Attar-Namdar M, Chourasia M, Cascio MG, Shurki A, Tam J, Neuman M, Rimmerman N, Vogel Z, Shteyer A, Pertwee RG, Zimmer A, Kogan NM, Bab I, Gabet Y (2022) Osteogenic growth peptide is a potent anti-inflammatory and bone preserving hormone via cannabinoid receptor type 2. Elife 11:e65834. s://doi.org/10.7554/eLife.65834

Martinez Ramirez CE, Ruiz-Pérez G, Stollenwerk TM, Behlke C, Doherty A, Hillard CJ (2023) Endocannabinoid signaling in the central nervous system. Glia 71:5–35. s://doi.org/10.1002/glia.24280

Dror RO, Green HF, Valant C, Borhani DW, Valcourt JR, Pan AC, Arlow DH, Canals M, Lane JR, Rahmani R, Baell JB, Sexton PM, Christopoulos A, Shaw DE (2013) Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature 503:295–299. s://doi.org/10.1038/nature12595

Hu J, Wang SZ, Forray C, el-Fakahany EE (1992) Complex allosteric modulation of cardiac muscarinic receptors by protamine: potential model for putative endogenous ligands. Mol Pharmacol 42:311–321.

Hu J, el-Fakahany EE (1993) Allosteric interaction of dynorphin and myelin basic protein with muscarinic receptors. Pharmacology 47(6):351–359. s://doi.org/10.1159/000139118

Karlsson E, Jolkkonen M, Mulugeta E, Onali P, Adem A (2000) Snake toxins with high selectivity for subtypes of muscarinic acetylcholine receptors. Biochimie 8:793–806. s://doi.org/10.1016/s0300-9084(00)01176-7

Jacoby DB, Gleich GJ, Fryer AD (993) Human eosinophil major basic protein is an endogenous allosteric antagonist at the inhibitory muscarinic M2 receptor. J Clin Invest 91:1314–1318. s://doi.org/10.1172/JCI116331

Yost BL, Gleich GJ, Fryer AD (1999) Ozone-induced hyperresponsiveness and blockade of M2 muscarinic receptors by eosinophil major basic protein. J Appl Physiol (1985) 87:1272–1278. s://doi.org/10.1152/jappl.1999.87.4.1272

Wang M, Yao Y, Kuang D, Hampson DR (2006) Activation of family C G-protein-coupled receptors by the tripeptide glutathione. J Biol Chem 281:8864–8870. s://doi.org/10.1074/jbc.M512865200

Broadhead GK, Mun HC, Avlani VA, Jourdon O, Church WB, Christopoulos A, Delbridge L, Conigrave AD (2011) Allosteric modulation of the calcium-sensing receptor by gamma-glutamyl peptides: inhibition of PTH secretion, suppression of intracellular cAMP levels, and a common mechanism of action with L-amino acids. J Biol Chem 286:8786–8797. s://doi.org/10.1074/jbc.M110.149724

Ward DT, Riccardi D (2012) New concepts in calcium-sensing receptor pharmacology and signalling. Br J Pharmacol 165:35–48. s://doi.org/10.1111/j.1476-5381.2011.01511.x

Tschammer N (2016) Allosteric Modulators of the Class A G Protein Coupled Receptors. Adv Exp Med Biol 917:185–207. s://doi.org/10.1007/978-3-319-32805-8_9

Skiba MA, Kruse AC (2021) Autoantibodies as Endogenous Modulators of GPCR Signaling. Trends Pharmacol Sci 42:135–150. s://doi.org/10.1016/j.tips.2020.11.013

Dahl L, Kotliar IB, Bendes A, Dodig-Crnković T, Fromm S, Elofsson A, Uhlén M, Sakmar TP, Schwenk JM (2023) Multiplexed selectivity screening of anti-GPCR antibodies. Sci Adv 9:eadf9297. s://doi.org/10.1126/sciadv.adf9297

Morshed SA, Ando T, Latif R, Davies TF (2010) Neutral antibodies to the TSH receptor are present in Graves' disease and regulate selective signaling cascades. Endocrinology 151:5537–5549. s://doi.org/10.1210/en.2010-0424

Sanders P, Young S, Sanders J, Kabelis K, Baker S, Sullivan A, Evans M, Clark J, Wilmot J, Hu X, Roberts E, Powell M, Núñez Miguel R, Furmaniak J, Rees Smith B (2011) Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol 46:81–99. s://doi.org/10.1530/JME-10-0127

Kifor O, McElduff A, LeBoff MS, Moore FD Jr, Butters R, Gao P, Cantor TL, Kifor I, Brown EM (2004) Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 89:548–556. s://doi.org/10.1210/jc.2003-031054

Fu ML, Herlitz H, Wallukat G, Hilme E, Hedner T, Hoebeke J, Hjalmarson A (1994) Functional autoimmune epitope on alpha 1-adrenergic receptors in patients with malignant hypertension. Lancet 344:1660–1663. s://doi.org/10.1016/s0140-6736(94)90456-1

Wallukat G, Wollenberger A, Morwinski R, Pitschner HF (1995) Anti-beta 1-adrenoceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: mapping of epitopes in the first and second extracellular loops. J Mol Cell Cardiol 27:397–406. s://doi.org/10.1016/s0022-2828(08)80036-3

Li H, Zuccolo J, Kem DC, Zillner C, Lee J, Smith K, James JA, Cunningham MW, Yu X (2013) Implications of a vasodilatory human monoclonal autoantibody in postural hypotension. J Biol Chem 288:30734–30741. s://doi.org/10.1074/jbc.M113.477869

Wallukat G, Fu HM, Matsui S, Hjalmarson A, Fu ML (1999) Autoantibodies against M2 muscarinic receptors in patients with cardiomyopathy display non-desensitized agonist-like effects. Life Sci 64:465–469. s://doi.org/10.1016/s0024-3205(98)00589-x

Tsuboi H, Matsumoto I, Wakamatsu E, Nakamura Y, Iizuka M, Hayashi T, Goto D, Ito S, Sumida T (2010) New epitopes and function of anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sjögren's syndrome. Clin Exp Immunol 162:53–61. s://doi.org/10.1111/j.1365-2249.2010.04188.x

Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jüpner A, Baur E, Nissen E, Vetter K, Neichel D, Dudenhausen JW, Haller H, Luft FC (1999) Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 103:945–952. s://doi.org/10.1172/JCI4106

Velloso EP, Pimentel RL, Braga JF, Cabral AC, Reis ZS, Bader M, Santos RA, Wallukat G (2016) Identification of a Novel Agonist-Like Autoantibody in Preeclamptic Patients. Am J Hypertens 29:405–412. s://doi.org/10.1093/ajh/hpv099

Eftekhari P, Sallé L, Lezoualc'h F, Mialet J, Gastineau M, Briand JP, Isenberg DA, Fournié GJ, Argibay J, Fischmeister R, Muller S, Hoebeke J (2000) Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block. Eur J Immunol 30:2782–2790. s://doi.org/10.1002/1521-4141(200010)30:10<2782::AID-IMMU2782>3.0.CO;2-9

Karczewski P, Hempel P, Kunze R, Bimmler M (2012) Agonistic autoantibodies to the α(1) -adrenergic receptor and the β(2) -adrenergic receptor in Alzheimer's and vascular dementia. Scand J Immunol 75:524–530. s://doi.org/10.1111/j.1365-3083.2012.02684.x

Macé G, Blanpied C, Emorine LJ, Druet P, Dietrich G (1999) Morphine-like activity of natural human IgG autoantibodies is because of binding to the first and third extracellular loops of the mu-opioid receptor. J Biol Chem 274:20079–20082. s://doi.org/10.1074/jbc.274.29.20079

Koo NY, Li J, Hwang SM, Choi SY, Lee SJ, Oh SB, Kim JS, Lee EB, Song YW, Park K (2008) Functional epitope of muscarinic type 3 receptor which interacts with autoantibodies from Sjogren's syndrome patients. Rheumatology (Oxford) 47:828–833. s://doi.org/10.1093/rheumatology/ken064

Cabral-Marques O, Marques A, Giil LM, De Vito R, Rademacher J, Günther J, Lange T, Humrich JY, Klapa S, Schinke S, Schimke LF, Marschner G, Pitann S, Adler S, Dechend R, Müller DN, Braicu I, Sehouli J, Schulze-Forster K, Trippel T, Scheibenbogen C, Staff A, Mertens PR, Löbel M, Mastroianni J, Plattfaut C, Gieseler F, Dragun D, Engelhardt BE, Fernandez-Cabezudo MJ, Ochs HD, Al-Ramadi BK, Lamprecht P, Mueller A, Heidecke H, Riemekasten G (2018) GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. Nat Commun 9:5224. s://doi.org/10.1038/s41467-018-07598-9

Zweck E, Karschnia M, Scheiber D, Heidecke H, Dechend R, Barthuber C, Kaufmann S, Kelm M, Roden M, Westenfeld R, Szendrödi J, Boege F (2023) Receptor autoantibodies: Associations with cardiac markers, histology, and function in human non-ischaemic heart failure. ESC Heart Fail 10:1258–1269. s://doi.org/10.1002/ehf2.14293

Bornholz B, Roggenbuck D, Jahns R, Boege F (2014) Diagnostic and therapeutic aspects of β1-adrenergic receptor autoantibodies in human heart disease. Autoimmun Rev 13:954–962. s://doi.org/10.1016/j.autrev.2014.08.021

Tang WHW, Naga Prasad SV (2022) Autoantibodies and Cardiomyopathy: Focus on Beta-1 Adrenergic Receptor Autoantibodies. J Cardiovasc Pharmacol 80:354–363. s://doi.org/10.1097/FJC.0000000000001264

Macé G, Jaume M, Blanpied C, Stephan L, Coudert JD, Druet P, Dietrich G (2002) Anti-mu-opioid-receptor IgG antibodies are commonly present in serum from healthy blood donors: evidence for a role in apoptotic immune cell death. Blood 100:3261–3268. s://doi.org/10.1182/blood-2002-01-0055

Ranganathan P, Chen H, Adelman MK, Schluter SF (2009) Autoantibodies to the delta-opioid receptor function as opioid agonists and display immunomodulatory activity. J Neuroimmunol 217:65–73. s://doi.org/10.1016/j.jneuroim.2009.10.007

Lopalco L, Barassi C, Pastori C, Longhi R, Burastero SE, Tambussi G, Mazzotta F, Lazzarin A, Clerici M, Siccardi AG (2000) CCR5-reactive antibodies in seronegative partners of HIV-seropositive individuals down-modulate surface CCR5 in vivo and neutralize the infectivity of R5 strains of HIV-1 In vitro. J Immunol 164:3426–3433. s://doi.org/10.4049/jimmunol.164.6.3426

Bouhlal H, Hocini H, Quillent-Grégoire C, Donkova V, Rose S, Amara A, Longhi R, Haeffner-Cavaillon N, Beretta A, Kaveri SV, Kazatchkine MD (2001) Antibodies to C-C chemokine receptor 5 in normal human IgG block infection of macrophages and lymphocytes with primary R5-tropic strains of HIV-1. J Immunol 166:7606–7611. s://doi.org/10.4049/jimmunol.166.12.7606

Bomsel M, Pastori C, Tudor D, Alberti C, Garcia S, Ferrari D, Lazzarin A, Lopalco L (2007) Natural mucosal antibodies reactive with first extracellular loop of CCR5 inhibit HIV-1 transport across human epithelial cells. AIDS 21:13–22. s://doi.org/10.1097/QAD.0b013e328011049b

Pastori C, Weiser B, Barassi C, Uberti-Foppa C, Ghezzi S, Longhi R, Calori G, Burger H, Kemal K, Poli G, Lazzarin A, Lopalco L (2006) Long-lasting CCR5 internalization by antibodies in a subset of long-term nonprogressors: a possible protective effect against disease progression. Blood 107:4825–4833. s://doi.org/10.1182/blood-2005-06-2463

Cao N, Chen H, Bai Y, Yang X, Xu W, Hao W, Zhou Y, Chai J, Wu Y, Wang Z, Yin X, Wang L, Wang W, Liu H, Fu MLX (2018) β2-adrenergic receptor autoantibodies alleviated myocardial damage induced by β1-adrenergic receptor autoantibodies in heart failure. Cardiovasc Res 114:1487–1498. s://doi.org/10.1093/cvr/cvy105

Tutor AS, Penela P, Mayor F Jr (2007) Anti-beta1-adrenergic receptor autoantibodies are potent stimulators of the ERK1/2 pathway in cardiac cells. Cardiovasc Res 76:51–60. s://doi.org/10.1016/j.cardiores.2007.05.022

Zimering MB (2017) Diabetes Autoantibodies Mediate Neural- and Endothelial Cell- Inhibitory Effects Via 5-Hydroxytryptamine- 2 Receptor Coupled to Phospholipase C/Inositol Triphosphate/Ca2+ Pathway. J Endocrinol Diabetes 4:10.15226/2374–6890/4/4/00184. s://doi.org/10.15226/2374-6890/4/4/00184

Zimering MB, Nadkarni SG (2019) Schizophrenia Plasma Autoantibodies Promote 'Biased Agonism' at the 5-Hydroxytryptamine 2A Receptor: Neurotoxicity is Positively Modulated by Metabotropic Glutamate 2/3 Receptor Agonism. Endocrinol Diabetes Metab J 3(4):http://researchopenworld.com/wp-content/uploads/2019/08/EDMJ-2019-117-Mark-Zimering-USA.pdf. ://researchopenworld.com/wp-content/uploads/2019/08/EDMJ-2019-117-Mark-Zimering-USA.pdf

Makita N, Sato J, Manaka K, Shoji Y, Oishi A, Hashimoto M, Fujita T, Iiri T (2007) An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations. Proc Natl Acad Sci U S A 104:5443–5448. s://doi.org/10.1073/pnas.0701290104

Makita N, Ando T, Sato J, Manaka K, Mitani K, Kikuchi Y, Niwa T, Ootaki M, Takeba Y, Matsumoto N, Kawakami A, Ogawa T, Nangaku M, Iiri T (2019) Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody. JCI Insight 4:e126449. https://doi.org/10.1172/jci.insight.126449

Venuti A, Pastori C, Siracusano G, Riva A, Sciortino MT, Lopalco L (2015) ERK1-Based Pathway as a New Selective Mechanism To Modulate CCR5 with Natural Antibodies. J Immunol 195:3045–3957. s://doi.org/10.4049/jimmunol.1500708

Spatola M, Sabater L, Planagumà J, Martínez-Hernandez E, Armangué T, Prüss H, Iizuka T, Caparó Oblitas RL, Antoine JC, Li R, Heaney N, Tubridy N, Munteis Olivas E, Rosenfeld MR, Graus F, Dalmau J (2018) Encephalitis with mGluR5 antibodies: Symptoms and antibody effects. Neurology 90:e1964-e1972. s://doi.org/10.1212/WNL.0000000000005614

Magnusson Y, Marullo S, Hoyer S, Waagstein F, Andersson B, Vahlne A, Guillet JG, Strosberg AD, Hjalmarson A, Hoebeke J (1990) Mapping of a functional autoimmune epitope on the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy. J Clin Invest 86:1658–1663. s://doi.org/10.1172/JCI114888

Wallukat G, Schimke I (2014) Agonistic autoantibodies directed against G-protein-coupled receptors and their relationship to cardiovascular diseases. Semin Immunopathol 36:351–363. s://doi.org/10.1007/s00281-014-0425-9

Wölfel A, Sättele M, Zechmeister C, Nikolaev VO, Lohse MJ, Boege F, Jahns R, Boivin-Jahns V (2020) Unmasking features of the auto-epitope essential for β1 -adrenoceptor activation by autoantibodies in chronic heart failure. ESC Heart Fail 7:1830–1841. https://doi.org/10.1002/ehf2.12747

Boivin V, Beyersdorf N, Palm D, Nikolaev VO, Schlipp A, Müller J, Schmidt D, Kocoski V, Kerkau T, Hünig T, Ertl G, Lohse MJ, Jahns R (2015) Novel receptor-derived cyclopeptides to treat heart failure caused by anti-β1-adrenoceptor antibodies in a human-analogous rat model. PLoS One 10:e0117589. s://doi.org/10.1371/journal.pone.0117589

Dong Y, Bai Y, Zhang S, Xu W, Xu J, Zhou Y, Zhang S, Wu Y, Yu H, Cao N, Liu H, Wang W (2019) Cyclic peptide RD808 reduces myocardial injury induced by β1-adrenoreceptor autoantibodies. Heart Vessels 34:1040–1051. s://doi.org/10.1007/s00380-018-1321-3

Derkach KV, Shpakova EA, Zharova OA, Shpakov AO (2014) The metabolic changes in rats immunized with BSA conjugate of peptides derived from the N-terminal region of type 4 melanocortin receptor. Dokl Biochem Biophys 458:163–166. s://doi.org/10.1134/S1607672914050019

Деркач КВ, Шпакова ЕА, Жарова ОА, Бондарева ВМ, Шпаков АО (2014) Влияние иммунизации крыс БСА-конъюгированным пептидом 269–280 меланокортинового рецептора 3-го типа на метаболические показатели и функции щитовидной железы. Цитология 56:850–857. [Derkach KV, Shpakova EA, Zharova OA, Bondareva VM, Shpakov AO (2014) [The influence of immunization of rats with BSA-conjugated peptide 269-280 of type 3 melanocortin receptor on the metabolic parameters and thyroid functions]. Tsitologiia. 56:850–857. (In Russ)].

Деркач КВ, Мойсеюк ИВ, Шпакова ЕА, Шпаков АО (2015) Тиреоидный статус у крыс, иммунизированных пептидами, производными внеклеточных участков меланокортиновых рецепторов 3-го и 4-го типов и серотонинового рецептора 1B-подтипа. Журн эволюц биохим физиол 51:243–250. [Derkach KV, Moyseuk IV, Shpakova EA, Sphakov AO (2015) [The thyroid status of rats immunized with peptides derived from the extracellular regions of the types 3 and 4 melanocortin receptors and the 1B-subtype 5-hydroxytryptamine receptor]. Zh Evol Biokhim Fiziol 51:243–250. (In Russ)].

Hofbauer KG, Lecourt AC, Peter JC (2008) Antibodies as pharmacologic tools for studies on the regulation of energy balance. Nutrition 24:791–797. s://doi.org/10.1016/j.nut.2008.06.001

Peter JC, Bekel A, Lecourt AC, Zipfel G, Eftekhari P, Nesslinger M, Breidert M, Muller S, Kessler L, Hofbauer KG (2009) Anti-melanocortin-4 receptor autoantibodies in obesity. J Clin Endocrinol Metab 94:793–800. s://doi.org/10.1210/jc.2008-1749

Peter JC, Lecourt AC, Weckering M, Zipfel G, Niehoff ML, Banks WA, Hofbauer KG (2010) A pharmacologically active monoclonal antibody against the human melanocortin-4 receptor: effectiveness after peripheral and central administration. J Pharmacol Exp Ther 333:478–390. s://doi.org/10.1124/jpet.109.163279

Nickols HH, Conn PJ (2014) Development of allosteric modulators of GPCRs for treatment of CNS disorders. Neurobiol Dis 61:55–71. s://doi.org/10.1016/j.nbd.2013.09.013

Walker LC, Lawrence AJ (2020) Allosteric modulation of muscarinic receptors in alcohol and substance use disorders. Adv Pharmacol 88:233–275. s://doi.org/10.1016/bs.apha.2020.01.003

Gregory KJ, Noetzel MJ, Niswender CM (2013) Pharmacology of metabotropic glutamate receptor allosteric modulators: structural basis and therapeutic potential for CNS disorders. Prog Mol Biol Transl Sci 115:61–121. s://doi.org/10.1016/B978-0-12-394587-7.00002-6

Bennett KA, Christopher JA, Tehan BG (2020) Structure-based discovery and development of metabotropic glutamate receptor 5 negative allosteric modulators. Adv Pharmacol 88:35–58. s://doi.org/10.1016/bs.apha.2020.03.001

Orgován Z, Ferenczy GG, Keserű GM (2021) Allosteric Molecular Switches in Metabotropic Glutamate Receptors. ChemMedChem 16:81–93. s://doi.org/10.1002/cmdc.202000444

Gómez-Santacana X, Panarello S, Rovira X, Llebaria A (2022) Photoswitchable allosteric modulators for metabotropic glutamate receptors. Curr Opin Pharmacol 66:102266. s://doi.org/10.1016/j.coph.2022.102266

Kaczor AA, Wróbel TM, Bartuzi D (2022) Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis. Molecules 28:178. s://doi.org/10.3390/molecules28010178

Obeng S, Hiranita T, León F, McMahon LR, McCurdy CR (2021) Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery. J Med Chem 64:6523–6548. s://doi.org/10.1021/acs.jmedchem.1c00028

Dopart R, Lu D, Lichtman AH, Kendall DA (2018) Allosteric modulators of cannabinoid receptor 1: developing compounds for improved specificity. Drug Metab Rev 50:3–13. s://doi.org/10.1080/03602532.2018.1428342

Gado F, Meini S, Bertini S, Digiacomo M, Macchia M, Manera C (2019) Allosteric modulators targeting cannabinoid cb1 and cb2 receptors: implications for drug discovery. Future Med Chem 11:2019–2037. s://doi.org/10.4155/fmc-2019-0005

Leo LM, Abood ME (2021) CB1 Cannabinoid Receptor Signaling and Biased Signaling. Molecules 26:5413. s://doi.org/10.3390/molecules26175413

Yuan J, Yang B, Hou G, Xie XQ, Feng Z (2023) Targeting the endocannabinoid system: Structural determinants and molecular mechanism of allosteric modulation. Drug Discov Today 28:103615. s://doi.org/10.1016/j.drudis.2023.103615

Root-Bernstein R (2022) Biased, Bitopic, Opioid-Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction. Pharmaceuticals (Basel) 15:214. s://doi.org/10.3390/ph15020214

Saito A, Alvi S, Valant C, Christopoulos A, Carbone SE, Poole DP (2022) Therapeutic potential of allosteric modulators for the treatment of gastrointestinal motility disorders. Br J Pharmacol 10.1111/bph.16023. Advance online publication. s://doi.org/10.1111/bph.16023

Bian Y, Jun JJ, Cuyler J, Xie XQ (2020) Covalent allosteric modulation: An emerging strategy for GPCRs drug discovery. Eur J Med Chem 206:112690. s://doi.org/10.1016/j.ejmech.2020.112690

Liu L, Lin L, Shen C, Rondard P, Pin JP, Xu C, Liu J (2023) Asymmetric activation of dimeric GABAB and metabotropic glutamate receptors. Am J Physiol Cell Physiol 325:C79–C89. s://doi.org/10.1152/ajpcell.00150.2022

Korkutata M, Agrawal L, Lazarus M (2022) Allosteric Modulation of Adenosine A2A Receptors as a New Therapeutic Avenue. Int J Mol Sci 23:2101. s://doi.org/10.3390/ijms23042101

Nguyen ATN, Tran QL, Baltos JA, McNeill SM, Nguyen DTN, May LT (2023) Small molecule allosteric modulation of the adenosine A1 receptor. Front Endocrinol (Lausanne) 14:1184360. s://doi.org/10.3389/fendo.2023.1184360

Blough B, Namjoshi O (2020) Small Molecule Neuropeptide S and Melanocortin 4 Receptor Ligands as Potential Treatments for Substance Use Disorders. Handb Exp Pharmacol 258:61–87. s://doi.org/10.1007/164_2019_313

Singh KD, Karnik SS (2022) Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric modulation in angiotensin receptors: IUPHAR Review 34. Br J Pharmacol 179:4461–4472. s://doi.org/10.1111/bph.15840

Malik F, Li Z (2022) Non-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes. Br J Pharmacol 179:511–525. s://doi.org/10.1111/bph.15446

Guan HP, Xiong Y (2022) Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders. Front Pharmacol 13:1043828. s://doi.org/10.3389/fphar.2022.1043828

Przegaliński E, Witek K, Wydra K, Kotlińska JH, Filip M (2023) 5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators. Nutrients 15:1449. s://doi.org/10.3390/nu15061449

Abouelasrar Salama S, Gouwy M, Van Damme J, Struyf S (2023) Acute-serum amyloid A and A-SAA-derived peptides as formyl peptide receptor (FPR) 2 ligands. Front Endocrinol (Lausanne) 14:1119227. s://doi.org/10.3389/fendo.2023.1119227

Borroto-Escuela DO, Cuesta-Marti C, Lopez-Salas A, Chruścicka-Smaga B, Crespo-Ramírez M, Tesoro-Cruz E, Palacios-Lagunas DA, Perez de la Mora M, Schellekens H, Fuxe K (2022) The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: potential relevance for brain and behavior. Front Mol Neurosci 15:1055344. s://doi.org/10.3389/fnmol.2022.1055344

Liu X, Lu S, Song K, Shen Q, Ni D, Li Q, He X, Zhang H, Wang Q, Chen Y, Li X, Wu J, Sheng C, Chen G, Liu Y, Lu X, Zhang J (2020) Unraveling allosteric landscapes of allosterome with ASD. Nucleic Acids Res 48:D394–D401. s://doi.org/10.1093/nar/gkz958

Cook AE, Mistry SN, Gregory KJ, Furness SG, Sexton PM, Scammells PJ, Conigrave AD, Christopoulos A, Leach K (2015) Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics. Br J Pharmacol 172:185–200. s://doi.org/10.1111/bph.12937

Li X, Ding W, Zhang H (2023) Cinacalcet use in secondary hyperparathyroidism: a machine learning-based systematic review. Front Endocrinol (Lausanne) 14:1146955. s://doi.org/10.3389/fendo.2023.1146955

Hoffmann K, Lutz DA, Straßburger J, Baqi Y, Müller CE, von Kügelgen I (2014) Competitive mode and site of interaction of ticagrelor at the human platelet P2Y12 -receptor. J Thromb Haemost 12:1898–1905. s://doi.org/10.1111/jth.12719

Parodi G, Dossi F, Raccis M, Talanas G, Mura E, Siciliano R, Guarino S, Marini A, Franca P, Saba PS, Sanna GD, Canonico ME (2023) Platelet inhibition with orodispersible ticagrelor in acute coronary syndromes according to morphine use: the TASTER study final results. Eur Heart J Cardiovasc Pharmacother 17:pvad061. s://doi.org/10.1093/ehjcvp/pvad061

Mandalaywala R, Rana A, Ramos AL, Sampson P, Ashkenas J (2023) Physical and pharmacokinetic characterization of Soluvec™, a novel, solvent-free aqueous ivermectin formulation. Ther Deliv 14:391–399. s://doi.org/10.4155/tde-2023-0021

Sagna AB, Zéla L, Ouedraogo COW, Pooda SH, Porciani A, Furnival-Adams J, Lado P, Somé AF, Pennetier C, Chaccour CJ, Dabiré RK, Mouline K (2023) Ivermectin as a novel malaria control tool: Getting ahead of the resistance curse. Acta Trop 245:106973. https://doi.org/10.1016/j.actatropica.2023.106973

Li XX, Lee JD, Massey NL, Guan C, Robertson AAB, Clark RJ, Woodruff TM (2020) Pharmacological characterisation of small molecule C5aR1 inhibitors in human cells reveals biased activities for signalling and function. Biochem Pharmacol 180:114156. s://doi.org/10.1016/j.bcp.2020.114156

Harigai M, Takada H (2022) Avacopan, a selective C5a receptor antagonist, for anti-neutrophil cytoplasmic antibody-associated vasculitis. Mod Rheumatol 32:475–483. s://doi.org/10.1093/mr/roab104

Lee A (2022) Avacopan: First Approval. Drugs 82:79–85. s://doi.org/10.1007/s40265-021-01643-6

Estrada JM, Soldin D, Buckey TM, Burman KD, Soldin OP (2014) Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice. Thyroid 24:411–423. s://doi.org/10.1089/thy.2013.0119

Kleinau G, Mueller S, Jaeschke H, Grzesik P, Neumann S, Diehl A, Paschke R, Krause G (2011) Defining structural and functional dimensions of the extracellular thyrotropin receptor region. J Biol Chem 286:22622–22631. s://doi.org/10.1074/jbc.M110.211193

Kleinau G, Hoyer I, Kreuchwig A, Haas AK, Rutz C, Furkert J, Worth CL, Krause G, Schülein R (2011) From molecular details of the interplay between transmembrane helices of the thyrotropin receptor to general aspects of signal transduction in family a G-protein-coupled receptors (GPCRs). J Biol Chem 286:25859–25871. s://doi.org/10.1074/jbc.M110.196980

Chantreau V, Taddese B, Munier M, Gourdin L, Henrion D, Rodien P, Chabbert M (2015) Molecular Insights into the Transmembrane Domain of the Thyrotropin Receptor. PLoS One 10:e0142250. s://doi.org/10.1371/journal.pone.0142250

Kleinau G, Haas AK, Neumann S, Worth CL, Hoyer I, Furkert J, Rutz C, Gershengorn MC, Schülein R, Krause G (2010) Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor. FASEB J 24:2347–2354. s://doi.org/10.1096/fj.09-149146

Kleinau G, Biebermann H (2014) Constitutive activities in the thyrotropin receptor: regulation and significance. Adv Pharmacol 70:81–119. s://doi.org/10.1016/B978-0-12-417197-8.00003-1

Kleinau G, Krause G (2009) Thyrotropin and homologous glycoprotein hormone receptors: structural and functional aspects of extracellular signaling mechanisms. Endocr Rev 30:133–151. s://doi.org/10.1210/er.2008-0044

Kleinau G, Neumann S, Grüters A, Krude H, Biebermann H (2013) Novel insights on thyroid-stimulating hormone receptor signal transduction. Endocr Rev 34:691–724. https://doi.org/10.1210/er.2012-1072

Costagliola S, Panneels V, Bonomi M, Koch J, Many MC, Smits G, Vassart G (2002) Tyrosine sulfation is required for agonist recognition by glycoprotein hormone receptors. EMBO J 21:504–513. s://doi.org/10.1093/emboj/21.4.504

Bonomi M, Busnelli M, Persani L, Vassart G, Costagliola S (2006) Structural differences in the hinge region of the glycoprotein hormone receptors: evidence from the sulfated tyrosine residues. Mol Endocrinol 20:3351–3363. s://doi.org/10.1210/me.2005-0521

Schaarschmidt J, Huth S, Meier R, Paschke R, Jaeschke H (2014) Influence of the hinge region and its adjacent domains on binding and signaling patterns of the thyrotropin and follitropin receptor. PLoS One 9:e111570. s://doi.org/10.1371/journal.pone.0111570

Krause G, Kreuchwig A, Kleinau G (2012) Extended and structurally supported insights into extracellular hormone binding, signal transduction and organization of the thyrotropin receptor. PLoS One 7:e52920. s://doi.org/10.1371/journal.pone.0052920

Schaarschmidt J, Nagel MBM, Huth S, Jaeschke H, Moretti R, Hintze V, von Bergen M, Kalkhof S, Meiler J, Paschke R (2016) Rearrangement of the Extracellular Domain/Extracellular Loop 1 Interface Is Critical for Thyrotropin Receptor Activation. J Biol Chem 291:14095–14108. s://doi.org/10.1074/jbc.M115.709659

Fokina EA, Shpakov AO (2022) Thyroid-stimulating hormone receptor: role in the development of thyroid pathology and its correction. J Evol Biochem Physiol 58:1439–1454. s://doi.org/10.1134/S0022093022050143

Jäschke H, Neumann S, Moore S, Thomas CJ, Colson AO, Costanzi S, Kleinau G, Jiang JK, Paschke R, Raaka BM, Krause G, Gershengorn MC (2006) A low molecular weight agonist signals by binding to the transmembrane domain of thyroid-stimulating hormone receptor (TSHR) and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). J Biol Chem 281:9841–9844. s://doi.org/10.1074/jbc.C600014200

Hoyer I, Haas AK, Kreuchwig A, Schülein R, Krause G (2013) Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists. Biochem Soc Trans 41:213–217. s://doi.org/10.1042/BST20120319

Kleinau G, Worth CL, Kreuchwig A, Biebermann H, Marcinkowski P, Scheerer P, Krause G (2017) Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work. Front Endocrinol (Lausanne) 8:86. s://doi.org/10.3389/fendo.2017.00086

Marcinkowski P, Kreuchwig A, Mendieta S, Hoyer I, Witte F, Furkert J, Rutz C, Lentz D, Krause G, Schülein R (2019) Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain. Mol Pharmacol 96:452–462. s://doi.org/10.1124/mol.119.116947

Mezei M, Latif R, Das B, Davies TF (2021) Implications of an Improved Model of the TSH Receptor Transmembrane Domain (TSHR-TMD-TRIO). Endocrinology 162:bqab051. https://doi.org/10.1210/endocr/bqab051

Latif R, Morshed SA, Ma R, Tokat B, Mezei M, Davies TF (2020) A Gq Biased Small Molecule Active at the TSH Receptor. Front Endocrinol (Lausanne) 11:372. https://doi.org/10.3389/fendo.2020.00372

Neumann S, Huang W, Titus S, Krause G, Kleinau G, Alberobello AT, Zheng W, Southall NT, Inglese J, Austin CP, Celi FS, Gavrilova O, Thomas CJ, Raaka BM, Gershengorn MC (2009) Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice. Proc Natl Acad Sci U S A 106:12471–12476. s://doi.org/10.1073/pnas.0904506106

Neumann S, Gershengorn MC (2011) Small molecule TSHR agonists and antagonists. Ann Endocrinol (Paris) 72:74–76. s://doi.org/10.1016/j.ando.2011.03.002

Gershengorn MC, Neumann S (2012) Update in TSH receptor agonists and antagonists. J Clin Endocrinol Metab 97:4287–4292. s://doi.org/10.1210/jc.2012-3080

Allen MD, Neumann S, Gershengorn MC (2011) Small-molecule thyrotropin receptor agonist activates naturally occurring thyrotropin-insensitive mutants and reveals their distinct cyclic adenosine monophosphate signal persistence. Thyroid 21:907–912. https://doi.org/10.1089/thy.2011.0025

Bakhtyukov AA, Derkach KV, Fokina EA, Sorokoumov VN, Zakharova IO, Bayunova LV, Shpakov AO (2022) Development of Low-Molecular-Weight Allosteric Agonist of Thyroid-Stimulating Hormone Receptor with Thyroidogenic Activity. Dokl Biochem Biophys 503:67–70. s://doi.org/10.1134/S1607672922020016

Shpakova EA, Shpakov AO, Chistyakova OV, Moyseyuk IV, Derkach KV (2012) Biological activity in vitro and in vivo of peptides corresponding to the third intracellular loop of thyrotropin receptor. Dokl Biochem Biophys 443:64–67. s://doi.org/10.1134/S1607672912020020

Derkach KV, Shpakova EA, Titov AM, Shpakov AO (2015) Intranasal and intramuscular administration of lysine-palmitoylated peptide 612-627 of thyroid-stimulating hormone receptor increases the level of thyroid hormones in rats. Int J Pept Res Ther 21:249–260. s://doi.org/10.1007/s10989-014-9452-6

Neumann S, Eliseeva E, Boutin A, Barnaeva E, Ferrer M, Southall N, Kim D, Hu X, Morgan SJ, Marugan JJ, Gershengorn MC (2018) Discovery of a Positive Allosteric Modulator of the Thyrotropin Receptor: Potentiation of Thyrotropin-Mediated Preosteoblast Differentiation In Vitro. J Pharmacol Exp Ther 364:38–45. s://doi.org/10.1124/jpet.117.244095

Neumann S, Kleinau G, Costanzi S, Moore S, Jiang JK, Raaka BM, Thomas CJ, Krause G, Gershengorn MC (2008) A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism. Endocrinology 149:5945–5950. s://doi.org/10.1210/en.2008-0836

Turcu AF, Kumar S, Neumann S, Coenen M, Iyer S, Chiriboga P, Gershengorn MC, Bahn RS (2013) A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J Clin Endocrinol Metab 98:2153–2159. s://doi.org/10.1210/jc.2013-1149

Neumann S, Nir EA, Eliseeva E, Huang W, Marugan J, Xiao J, Dulcey AE, Gershengorn MC (2014) A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology 155:310–314. s://doi.org/10.1210/en.2013-1835

Derkach KV, Fokina EA, Bakhtyukov AA, Sorokoumov VN, Stepochkina AM, Zakharova IO, Shpakov AO (2022) The Study of Biological Activity of a New Thieno[2,3-D]-Pyrimidine-Based Neutral Antagonist of Thyrotropin Receptor. Bull Exp Biol Med 172:713–717. s://doi.org/10.1007/s10517-022-05462-x

Marcinkowski P, Hoyer I, Specker E, Furkert J, Rutz C, Neuenschwander M, Sobottka S, Sun H, Nazare M, Berchner-Pfannschmidt U, von Kries JP, Eckstein A, Schülein R, Krause G (2019) A New Highly Thyrotropin Receptor-Selective Small-Molecule Antagonist with Potential for the Treatment of Graves' Orbitopathy. Thyroid 29:111–123. s://doi.org/10.1089/thy.2018.0349

Neumann S, Huang W, Eliseeva E, Titus S, Thomas CJ, Gershengorn MC (2010) A small molecule inverse agonist for the human thyroid-stimulating hormone receptor. Endocrinology 151:3454–3459. s://doi.org/10.1210/en.2010-0199

Neumann S, Eliseeva E, McCoy JG, Napolitano G, Giuliani C, Monaco F, Huang W, Gershengorn MC (2011) A new small-molecule antagonist inhibits Graves' disease antibody activation of the TSH receptor. J Clin Endocrinol Metab 96:548–554. s://doi.org/10.1210/jc.2010-1935

Neumann S, Pope A, Geras-Raaka E, Raaka BM, Bahn RS, Gershengorn MC (2012) A drug-like antagonist inhibits thyrotropin receptor-mediated stimulation of cAMP production in Graves' orbital fibroblasts. Thyroid 22:839–843. s://doi.org/10.1089/thy.2011.0520

Derkach KV, Bakhtyukov AA, Sorokoumov VN, Shpakov AO (2020) New Thieno-[2,3-d]pyrimidine-Based Functional Antagonist for the Receptor of Thyroid Stimulating Hormone. Dokl Biochem Biophys 491:77–80. s://doi.org/10.1134/S1607672920020064

Galofré JC, Chacón AM, Latif R (2013) Targeting thyroid diseases with TSH receptor analogs. Endocrinol Nutr 60:590–598. s://doi.org/10.1016/j.endonu.2012.12.008

Shpakov AO (2021) Endogenous and Synthetic Regulators of the Peripheral Components of the Hypothalamo-Hypophyseal-Gonadal and -Thyroid Axes. Neurosci Behav Physiol 51:332–345. s://doi.org/10.1007/s11055-021-01076-4

Kim SM, Ryu V, Miyashita S, Korkmaz F, Lizneva D, Gera S, Latif R, Davies TF, Iqbal J, Yuen T, Zaidi M (2021) Thyrotropin, Hyperthyroidism, and Bone Mass. J Clin Endocrinol Metab 106:e4809–e4821. s://doi.org/10.1210/clinem/dgab548

Davis PJ, Hercbergs A, Luidens MK, Lin HY (2015) Recurrence of differentiated thyroid carcinoma during full TSH suppression: is the tumor now thyroid hormone dependent? Horm Cancer 6:7–12. s://doi.org/10.1007/s12672-014-0204-z

Boutin A, Neumann S, Gershengorn MC (2016) Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells. Endocrinology 157:2173–2181. s://doi.org/10.1210/en.2015-2040

Boutin A, Gershengorn MC, Neumann S (2020) β-Arrestin 1 in Thyrotropin Receptor Signaling in Bone: Studies in Osteoblast-Like Cells. Front Endocrinol (Lausanne) 11:312. s://doi.org/10.3389/fendo.2020.00312

Bahn RS (2012) Autoimmunity and Graves' disease. Clin Pharmacol Ther 91:577–579. s://doi.org/10.1038/clpt.2012.10

Ryder M, Wentworth M, Algeciras-Schimnich A, Morris JC, Garrity J, Sanders J, Young S, Sanders P, Furmaniak J, Rees Smith B (2021) Blocking the Thyrotropin Receptor with K1-70 in a Patient with Follicular Thyroid Cancer, Graves' Disease, and Graves' Ophthalmopathy. Thyroid 31:1597–1602. s://doi.org/10.1089/thy.2021.0053

Cui X, Wang F, Liu C (2023) A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves' orbitopathy. Front Immunol 14:1062045. s://doi.org/10.3389/fimmu.2023.1062045

Lane JR, IJzerman AP (2013) Allosteric approaches to GPCR drug discovery. Drug Discov Today Technol 10:e219–21. s://doi.org/10.1016/j.ddtec.2013.01.006

Lane LC, Cheetham TD, Perros P, Pearce SHS (2020) New Therapeutic Horizons for Graves' Hyperthyroidism. Endocr Rev 41:873–884. s://doi.org/10.1210/endrev/bnaa022

Hamidi S, Hofmann MC, Iyer PC, Cabanillas ME, Hu MI, Busaidy NL, Dadu R (2023) Review article: new treatments for advanced differentiated thyroid cancers and potential mechanisms of drug resistance. Front Endocrinol (Lausanne) 14:1176731. s://doi.org/10.3389/fendo.2023.1176731

Wiersinga WM (2011) Autoimmunity in Graves' ophthalmopathy: the result of an unfortunate marriage between TSH receptors and IGF-1 receptors? J Clin Endocrinol Metab 96:2386–2394. s://doi.org/10.1210/jc.2011-0307

Krause G, Eckstein A, Schülein R (2020) Modulating TSH Receptor Signaling for Therapeutic Benefit. Eur Thyroid J 9(Suppl 1):66–77. s://doi.org/10.1159/000511871

O'Callaghan K, Kuliopulos A, Covic L (2012) Turning receptors on and off with intracellular pepducins: new insights into G-protein-coupled receptor drug development. J Biol Chem 287(16):12787–12796. s://doi.org/10.1074/jbc.R112.355461

Zhang P, Covic L, Kuliopulos A (2015) Pepducins and Other Lipidated Peptides as Mechanistic Probes and Therapeutics. Methods Mol Biol 1324:191–203. s://doi.org/10.1007/978-1-4939-2806-4_13

Michael E, Covic L, Kuliopulos A (2022) Lipopeptide Pepducins as Therapeutic Agents. Methods Mol Biol 2383:307–333. s://doi.org/10.1007/978-1-0716-1752-6_21

Xu H, Tilley DG (2022) Pepducin-mediated G Protein-Coupled Receptor Signaling in the Cardiovascular System. J Cardiovasc Pharmacol 80:378–385. s://doi.org/10.1097/FJC.0000000000001236

Shpakov AO, Gur'yanov IA, Kuznetsova LA, Plesneva SA, Shpakova EA, Vlasov GP, Pertseva MN (2007) Studies of the molecular mechanisms of action of relaxin on the adenylyl cyclase signaling system using synthetic peptides derived from the LGR7 relaxin receptor. Neurosci Behav Physiol 37:705–714. s://doi.org/10.1007/s11055-007-0071-y

Shpakov AO, Shpakova EA, Tarasenko II, Derkach KV, Vlasov GP (2010) The peptides mimicking the third intracellular loop of 5-hydroxytryptamine receptors of the types 1B and 6 selectively activate G proteins and receptor-specifically inhibit serotonin signaling via the adenylyl cyclase system. Int J Pept Res Ther 16:95–105. s://doi.org/10.1007/s10989-9208-x

Шпакова ЕА, Скворцова ЕА, Тарасенко ИИ, Шпаков АО (2012) Вторичная структура пептидов, производных третьей петли рецепторов серпантинного типа, и ее связь с их биологической активностью. Цитология 54:119–129. [Shpakova EA, Skvortsova EA, Tarasenko II, Shpakov AO (2012) [The secondary structure of peptides derived from the third intracellular loop of the serpentine type receptors and its interrelation with their biological activity]. Tsitologiia 54:119–129. (In Russ)].

Puett D, Li Y, DeMars G, Angelova K, Fanelli F (2007) A functional transmembrane complex: the luteinizing hormone receptor with bound ligand and G protein. Mol Cell Endocrinol 260-262:126–136. s://doi.org/10.1016/j.mce.2006.05.009

Puett D, Angelova K, da Costa MR, Warrenfeltz SW, Fanelli F (2010) The luteinizing hormone receptor: insights into structure-function relationships and hormone-receptor-mediated changes in gene expression in ovarian cancer cells. Mol Cell Endocrinol 329:47–55. s://doi.org/10.1016/j.mce.2010.04.025

Duan J, Xu P, Cheng X, Mao C, Croll T, He X, Shi J, Luan X, Yin W, You E, Liu Q, Zhang S, Jiang H, Zhang Y, Jiang Y, Xu HE (2021) Structures of full-length glycoprotein hormone receptor signalling complexes. Nature 598:688–692. s://doi.org/10.1038/s41586-021-03924-2

Riccetti L, Yvinec R, Klett D, Gallay N, Combarnous Y, Reiter E, Simoni M, Casarini L, Ayoub MA (2017) Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors. Sci Rep 7(1):940. https://doi.org/10.1038/s41598-017-01078-8

Segaloff DL (2009) Diseases associated with mutations of the human lutropin receptor. Prog Mol Biol Transl Sci 89:97–114. s://doi.org/10.1016/S1877-1173(09)89004-2

Latronico AC, Arnhold IJ (2012) Inactivating mutations of the human luteinizing hormone receptor in both sexes. Semin Reprod Med 30:382–386. s://doi.org/10.1055/s-0032-1324721

Bhattacharya I, Dey S, Banerjee A (2023) Revisiting the gonadotropic regulation of mammalian spermatogenesis: evolving lessons during the past decade. Front Endocrinol (Lausanne) 14:1110572. s://doi.org/10.3389/fendo.2023.1110572

Althumairy D, Zhang X, Baez N, Barisas G, Roess DA, Bousfield GR, Crans DC (2020) Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors. Diseases 8:35. s://doi.org/10.3390/diseases8030035 .

Fournier T, Guibourdenche J, Evain-Brion D (2015) Review: hCGs: different sources of production, different glycoforms and functions. Placenta 36 Suppl 1:S60–S65. https://doi.org/10.1016/j.placenta.2015.02.002

Fournier T (2016) Human chorionic gonadotropin: Different glycoforms and biological activity depending on its source of production. Ann Endocrinol (Paris) 77:75–81. https://doi.org/10.1016/j.ando.2016.04.012

Casarini L, Simoni M (2021) Recent advances in understanding gonadotropin signaling. Fac Rev 10:41. s://doi.org/10.12703/r/10-41

Tao YX, Johnson NB, Segaloff DL (2004) Constitutive and agonist-dependent self-association of the cell surface human lutropin receptor. J Biol Chem 279:5904–5914. https://doi.org/10.1074/jbc.M311162200

Guan R, Feng X, Wu X, Zhang M, Zhang X, Hébert TE, Segaloff DL (2009) Bioluminescence resonance energy transfer studies reveal constitutive dimerization of the human lutropin receptor and a lack of correlation between receptor activation and the propensity for dimerization. J Biol Chem 284:7483–7494. https://doi.org/10.1074/jbc.M809150200

Zhang M, Feng X, Guan R, Hébert TE, Segaloff DL (2009) A cell surface inactive mutant of the human lutropin receptor (hLHR) attenuates signaling of wild-type or constitutively active receptors via heterodimerization. Cell Signal 21:1663–1671. https://doi.org/10.1016/j.cellsig.2009.07.003

Jeoung M, Lee C, Ji I, Ji TH (2007) Trans-activation, cis-activation and signal selection of gonadotropin receptors. Mol Cell Endocrinol 260–262:137–143. https://doi.org/10.1016/j.mce.2005.09.015

Fanelli F, De Benedetti PG, Raimondi F, Seeber M (2009) Computational modeling of intramolecular and intermolecular communication in GPCRs. Curr Protein Pept Sci 10:173–185. s://doi.org/10.2174/138920309787847554

Rivero-Müller A, Chou YY, Ji I, Lajic S, Hanyaloglu AC, Jonas K, Rahman N, Ji TH, Huhtaniemi I (2010) Rescue of defective G protein-coupled receptor function in vivo by intermolecular cooperation. Proc Natl Acad Sci U S A 107:2319–2324. https://doi.org/10.1073/pnas.0906695106

Feng X, Zhang M, Guan R, Segaloff DL (2013) Heterodimerization between the lutropin and follitropin receptors is associated with an attenuation of hormone-dependent signaling. Endocrinology 154:3925–3930. s://doi.org/10.1210/en.2013-1407

Mazurkiewicz JE, Herrick-Davis K, Barroso M, Ulloa-Aguirre A, Lindau-Shepard B, Thomas RM, Dias JA (2015) Single-molecule analyses of fully functional fluorescent protein-tagged follitropin receptor reveal homodimerization and specific heterodimerization with lutropin receptor. Biol Reprod 92:100. s://doi.org/10.1095/biolreprod.114.125781

Jonas KC, Chen S, Virta M, Mora J, Franks S, Huhtaniemi I, Hanyaloglu AC (2018) Temporal reprogramming of calcium signalling via crosstalk of gonadotrophin receptors that associate as functionally asymmetric heteromers. Sci Rep 8:2239. s://doi.org/10.1038/s41598-018-20722-5

Szymańska K, Kałafut J, Przybyszewska A, Paziewska B, Adamczuk G, Kiełbus M, Rivero-Müller A (2018) FSHR Trans-Activation and Oligomerization. Front Endocrinol (Lausanne) 9:760. s://doi.org/10.3389/fendo.2018.00760

Casarini L, Paradiso E, Lazzaretti C, D'Alessandro S, Roy N, Mascolo E, Zaręba K, García-Gasca A, Simoni M (2022) Regulation of antral follicular growth by an interplay between gonadotropins and their receptors. J Assist Reprod Genet 39:893–904. https://doi.org/10.1007/s10815-022-02456-6

Schniewind HA, Sattler LM, Haudum CW, Münzker J, Minich WB, Obermayer-Pietsch B, Schomburg L (2021) Autoimmunity to the Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone Receptor (LHR) in Polycystic Ovarian Syndrome. Int J Mol Sci 22:13667. s://doi.org/10.3390/ijms222413667

Chiauzzi VA, Bussmann L, Calvo JC, Sundblad V, Charreau EH (2004) Circulating immunoglobulins that inhibit the binding of follicle-stimulating hormone to its receptor: a putative diagnostic role in resistant ovary syndrome? Clin Endocrinol (Oxf) 61:46–54. s://doi.org/10.1111/j.1365-2265.2004.02054.x

Riestenberg C, Ahern S, Shamonki M (2020) Follicle-stimulating hormone receptor autoantibody associated primary ovarian insufficiency successfully treated with corticosteroids: a case report. F S Rep 1:206–208. s://doi.org/10.1016/j.xfre.2020.09.002

Heitman LH, Oosterom J, Bonger KM, Timmers CM, Wiegerinck PH, Ijzerman AP (2008) [3H]Org 43553, the first low-molecular-weight agonistic and allosteric radioligand for the human luteinizing hormone receptor. Mol Pharmacol 73:518–524. https://doi.org/10.1124/mol.107.039875

van de Lagemaat R, Timmers CM, Kelder J, van Koppen C, Mosselman S, Hanssen RG (2009) Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor. Hum Reprod 24:640–648. https://doi.org/10.1093/humrep/den412

van de Lagemaat R, Raafs BC, van Koppen C, Timmers CM, Mulders SM, Hanssen RG (2011) Prevention of the onset of ovarian hyperstimulation syndrome (OHSS) in the rat after ovulation induction with a low molecular weight agonist of the LH receptor compared with hCG and rec-LH. Endocrinology 152:4350–4357. s://doi.org/10.1210/en.2011-1077

Gerrits M, Mannaerts B, Kramer H, Addo S, Hanssen R (2013) First evidence of ovulation induced by oral LH agonists in healthy female volunteers of reproductive age. J Clin Endocrinol Metab 98:1558–1566. s://doi.org/10.1210/jc.2012-3404

Shpakov AO, Dar'in DV, Derkach KV, Lobanov PS (2014) The stimulating influence of thienopyrimidine compounds on the adenylyl cyclase signaling systems in the rat testes. Dokl Biochem Biophys 456:104–107. s://doi.org/10.1134/S1607672914030065

Derkach KV, Dar'in DV, Lobanov PS, Shpakov AO (2014) Intratesticular, intraperitoneal, and oral administration of thienopyrimidine derivatives increases the testosterone level in male rats. Dokl Biol Sci 459:326–329. s://doi.org/10.1134/S0012496614060040

Derkach KV, Legkodukh AS, Dar’in DV, Shpakov AO (2016) The stimulating effect of thienopyrimidines, the structural analogs of ORG 43553, on the activity of adenylyl cyclase in the testes and on the testosterone production in male rats. Tsitologiia 58:602–609.

Bakhtyukov AA, Derkach KV, Dar'in DV, Shpakov AO (2019) Conservation of Steroidogenic Effect of the Low-Molecular-Weight Agonist of Luteinizing Hormone Receptor in the Course of Its Long-Term Administration to Male Rats. Dokl Biochem Biophys 484:78–81. s://doi.org/10.1134/S1607672919010216

Bakhtyukov AA, Derkach KV, Gureev MA, Dar'in DV, Sorokoumov VN, Romanova IV, Morina IY, Stepochkina AM, Shpakov AO (2020) Comparative Study of the Steroidogenic Effects of Human Chorionic Gonadotropin and Thieno[2,3-D]pyrimidine-Based Allosteric Agonist of Luteinizing Hormone Receptor in Young Adult, Aging and Diabetic Male Rats. Int J Mol Sci 21:7493. s://doi.org/10.3390/ijms21207493

Bakhtyukov AA, Derkach KV, Sorokoumov VN, Stepochkina AM, Romanova IV, Morina IY, Zakharova IO, Bayunova LV, Shpakov AO (2021) The Effects of Separate and Combined Treatment of Male Rats with Type 2 Diabetes with Metformin and Orthosteric and Allosteric Agonists of Luteinizing Hormone Receptor on Steroidogenesis and Spermatogenesis. Int J Mol Sci 23:198. s://doi.org/10.3390/ijms23010198

Derkach KV, Bakhtyukov AA, Morina IY, Romanova IV, Bayunova LV, Shpakov AO (2022) Comparative Study of the Restoring Effect of Metformin, Gonadotropin, and Allosteric Agonist of Luteinizing Hormone Receptor on Spermatogenesis in Male Rats with Streptozotocin-Induced Type 2 Diabetes Mellitus. Bull Exp Biol Med 172:435–440. s://doi.org/10.1007/s10517-022-05409-2

Fokina EA, Derkach KV, Bakhtyukov AA, Sorokoumov VN, Lebedev IA, Morina IY, Shpakov AO (2022) Stimulation of Ovulation in Immature Female Rats Using Orthosteric and Allosteric Luteinizing Hormone Receptor Agonists. Dokl Biochem Biophys 507:345–349. s://doi.org/10.1134/S1607672922340063

Bakhtyukov AA, Derkach KV, Fokina EA, Lebedev IA, Sorokoumov VN, Bayunova LV, Shpakov AO (2023) Effect of Different Luteinizing Hormone Receptor Agonists on Ovarian Steroidogenesis in Mature Female Rats. J Evol Biochem Physiol 59:57–68. s://doi.org/10.1134/S0022093023010052

Jorand-Lebrun C, Brondyk B, Lin J, Magar S, Murray R, Reddy A, Shroff H, Wands G, Weiser W, Xu Q, McKenna S, Brugger N (2007) Identification, synthesis, and biological evaluation of novel pyrazoles as low molecular weight luteinizing hormone receptor agonists. Bioorg Med Chem Lett 17:2080–2085. s://doi.org/10.1016/j.bmcl.2006.12.062

Shpakova EA, Derkach KV, Shpakov AO (2013) Biological activity of lipophilic derivatives of peptide 562–572 of rat luteinizing hormone receptor. Dokl Biochem Biophys. 452:248–250. s://doi.org/10.1134/S1607672913050116

Шпакова ЕА, Шпаков АО (2013) Регуляция активности аденилатциклазы в семенниках крыс ацилированными производными пептида 562–572 рецептора лютеинизирующего гормона. Цитология. 55:737–744. [Shpakova EA, Shpakov AO (2013) [Regulation of adenylyl cyclase activity in the rat testes by acylated derivatives of peptide 562-572 of luteinizing hormone receptor]. Tsitologiia 55:737–744. (In Russ)].

Heitman LH, Narlawar R, de Vries H, Willemsen MN, Wolfram D, Brussee J, Ijzerman AP (2009) Substituted terphenyl compounds as the first class of low molecular weight allosteric inhibitors of the luteinizing hormone receptor. J Med Chem 52:2036–2042. https://doi.org/10.1021/jm801561h

Heitman LH, Kleinau G, Brussee J, Krause G, Ijzerman AP (2012) Determination of different putative allosteric binding pockets at the lutropin receptor by using diverse drug-like low molecular weight ligands. Mol Cell Endocrinol 351:326–336. s://doi.org/10.1016/j.mce.2012.01.010

Ayoub MA, Yvinec R, Jégot G, Dias JA, Poli SM, Poupon A, Crépieux P, Reiter E (2016) Profiling of FSHR negative allosteric modulators on LH/CGR reveals biased antagonism with implications in steroidogenesis. Mol Cell Endocrinol 436:10–22. s://doi.org/10.1016/j.mce.2016.07.013

Wortmann L, Lindenthal B, Muhn P, Walter A, Nubbemeyer R, Heldmann D, Sobek L, Morandi F, Schrey AK, Moosmayer D, Günther J, Kuhnke J, Koppitz M, Lücking U, Röhn U, Schäfer M, Nowak-Reppel K, Kühne R, Weinmann H, Langer G (2019) Discovery of BAY-298 and BAY-899: Tetrahydro-1,6-naphthyridine-Based, Potent, and Selective Antagonists of the Luteinizing Hormone Receptor Which Reduce Sex Hormone Levels in Vivo. J Med Chem 62:10321–10341. s://doi.org/10.1021/acs.jmedchem.9b01382

Munier M, Ayoub M, Suteau V, Gourdin L, Henrion D, Reiter E, Rodien P (2021) In vitro effects of the endocrine disruptor p,p'DDT on human choriogonadotropin/luteinizing hormone receptor signalling. Arch Toxicol 95:1671–1681. s://doi.org/10.1007/s00204-021-03007-1

Derkach KV, Bakhtyukov AA, Dar’in DV, Golovanova NE, Shpakov AO (2019) Novel Thienopyrimidine Derivatives with an Activity of Full and Inverse Agonists of the Luteinizing Hormone Receptor. J Evol Biochem Physiol 55:414–418. https://doi.org/10.1134/S0022093019050090

Derkach KV, Dar’in DV, Shpakov AO (2020) Low-Molecular-Weight Ligands of Luteinizing Hormone with the Activity of Antagonists. Biochemistry (Moscow). Suppl. Ser. A: Membrane and Cell Biology. 14:223–231. s://doi.org/10.1134/S1990747820030034

Heitman LH, Ijzerman AP (2008) G protein-coupled receptors of the hypothalamic-pituitary-gonadal axis: a case for Gnrh, LH, FSH, and GPR54 receptor ligands. Med Res Rev 28:975–1011. s://doi.org/10.1002/med.20129

Nataraja SG, Yu HN, Palmer SS (2015) Discovery and Development of Small Molecule Allosteric Modulators of Glycoprotein Hormone Receptors. Front Endocrinol (Lausanne) 6:142. s://doi.org/10.3389/fendo.2015.00142

Lazzaretti C, Simoni M, Casarini L, Paradiso E (2023) Allosteric modulation of gonadotropin receptors. Front Endocrinol (Lausanne) 14:1179079. s://doi.org/10.3389/fendo.2023.1179079

Gilchrist RL, Ryu KS, Ji I, Ji TH (1996) The luteinizing hormone/chorionic gonadotropin receptor has distinct transmembrane conductors for cAMP and inositol phosphate signals. J Biol Chem 271:19283–19287. s://doi.org/10.1074/jbc.271.32.19283

Derkach KV, Romanova IV, Bakhtyukov AA, Morina IY, Dar'in DV, Sorokoumov VN, Shpakov AO (2021) The Effect of Low-Molecular-Weight Allosteric Agonist of Luteinizing Hormone Receptor on Functional State of the Testes in Aging and Diabetic Rats. Bull Exp Biol Med 171:81–86. s://doi.org/10.1007/s10517-021-05177-5

Bakhtyukov AA, Morina IYu, Derkach KV, Romanova IV, Sorokoumov VN, Shpakov AO (2022) Development of approaches to reduce the effective dose of gonadotropin in the treatment in androgen insufficiency in male rats with type 1 diabetes mellitus. J Evol Biochem Physiol 58:1503–1513. s://doi.org/10.1134/S0022093022050209

Shpakov AO, Bakhtyukov AA, Dar’in DV, Derkach KV (2019) Pretreatment of rats with an allosteric luteinizing hormone receptor agonist augments chorionic gonadotropin-induced stimulation of testosterone production. J Evol Biochem Physiol 55:510–514. s://doi.org/10.1134/S0022093019060115

Derkach KV, Bakhtyukov AA, Romanova IV, Zorina II, Bayunova LV, Bondareva VM, Morina IYu, Roy VK, Shpakov AO (2020) The effect of metformin treatment on the basal and gonadotropin-stimulated steroidogenesis in male rats with type 2 diabetes mellitus. Andrologia. 52:e13816. s://doi.org/10.1111/and.13816

Shpakov AO (2021) Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms. Pharmaceuticals (Basel) 14:42. https://doi.org/10.3390/ph14010042

Shpakova EA, Sorokoumov VN, Akenti’ev AV, Derkach KV, Tennikova TB, Shpakov AO (2017) The relationship between physical-chemical characteristics and biological activity of peptide 562–572 of luteinizing hormone receptor modified by decanoyl radicals at the N- and C-termini. Tsitologiia 59:133–139.

Derkach KV, Shpakova EA, Shpakov AO (2014) Palmitoylated peptide 562–572 of luteinizing hormone receptor increases testosterone level in male rats. Bull Exp Biol Med 158:209–212. s://doi.org/10.1007/s10517-014-2724-5