ПЕРСПЕКТИВЫ ГЕННОЙ ТЕРАПИИ ЭПИЛЕПСИИ С ИСПОЛЬЗОВАНИЕМ ВЕКТОРОВ НА ОСНОВЕ КАЛЬЦИЙ-ЗАВИСИМЫХ КАЛИЕВЫХ КАНАЛОВ
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Ключевые слова

эпилепсия
генная терапия
SK-канал
IK-канал
BK-канал

Как цитировать

Никитин, Е. С., Балабан, П. М., & Зайцев , А. В. (2022). ПЕРСПЕКТИВЫ ГЕННОЙ ТЕРАПИИ ЭПИЛЕПСИИ С ИСПОЛЬЗОВАНИЕМ ВЕКТОРОВ НА ОСНОВЕ КАЛЬЦИЙ-ЗАВИСИМЫХ КАЛИЕВЫХ КАНАЛОВ. Российский физиологический журнал им. И. М. Сеченова, 108(7), 795–806. извлечено от https://rusjphysiol.org/index.php/rusjphysiol/article/view/1676

Аннотация

Эпилепсия является одним из распространённых неврологических заболеваний человека, при этом почти трети больных современные противосудорожные препараты не помогают полностью избавиться от эпилептических приступов. Поэтому поиск и разработка новых подходов лечения эпилепсии остается одной из актуальных проблем современной фундаментальной нейробиологии и клинической неврологии. В последние годы все большее внимание исследователей привлекает генная терапия эпилепсии. На сегодняшний день для генной терапии приоритетным направлением считается гиперэкспрессия каких-либо генов в нейронах, снижающих активность нейронных сетей в эпилептическом очаге, включая как экспрессию белков-каналов, так и тормозных нейромодуляторов. В данном обзоре мы рассматриваем возможность использования гиперэкспрессии кальций-зависимых калиевых каналов. Преимущество выбора данной подгруппы каналов для генной терапии может заключаться в том, что максимальная активация кальций-зависимых калиевых каналов и их гиперполяризующее действие реализуется при накоплении внутриклеточного кальция, что наблюдается при эпилептической активности в нейронных сетях. В клетках млекопитающих экспрессируется несколько подтипов кальций-зависимых калиевых каналов. Анализ имеющихся экспериментальных и клинических данных показывает, что каналы с промежуточной (IK-каналы) и малой проводимостью (SK-каналы) могут обладать высоким терапевтическим потенциалом для применения в генной терапии эпилепсии.

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Литература

Banerjee PN, Filippi D, Hauser AW (2009) The descriptive epidemiology of epilepsy—A review. Epilepsy Res 85:31–45.

https://doi.org/10.1016/j.eplepsyres.2009.03.003

Janmohamed M, Brodie MJ, Kwan P (2020) Pharmacoresistance – Epidemiology, mechanisms, and impact on epilepsy treatment. Neuropharmacology 168:107790.

https://doi.org/10.1016/j.neuropharm.2019.107790

Engel J (2018) The current place of epilepsy surgery. Curr Opin Neurol 31:192–197.

https://doi.org/10.1097/WCO.0000000000000528

Schramm J (2008) Temporal lobe epilepsy surgery and the quest for optimal extent of resection: a review. Epilepsia 49:1296–307.

https://doi.org/10.1111/j.1528-1167.2008.01604.x

Walker MC, Kullmann DM (2020) Optogenetic and chemogenetic therapies for epilepsy. Neuropharmacology 168:107751.

https://doi.org/10.1016/j.neuropharm.2019.107751

Simonato M (2014) Gene therapy for epilepsy. Epilepsy Behav 38:125–130.

https://doi.org/10.1016/j.yebeh.2013.09.013

Wang D, Gao G (2014) State-of-the-art human gene therapy: part II. Gene therapy strategies and clinical applications. Discov Med 18:151–161.

Thomas RH, Berkovic SF (2014) The hidden genetics of epilepsy—a clinically important new paradigm. Nat Rev Neurol 10:283–292.

https://doi.org/10.1038/nrneurol.2014.62

McCown TJ (2006) Adeno-associated Virus-Mediated Expression and Constitutive Secretion of Galanin Suppresses Limbic Seizure Activity in Vivo. Mol Ther 14:63–68.

https://doi.org/10.1016/J.YMTHE.2006.04.004

Noè F, Pool AH, Nissinen J, Gobbi M, Bland R, Rizzi M, Balducci C, Ferraguti F, Sperk G, During MJ, Pitkänen A, Vezzani A (2008) Neuropeptide Y gene therapy decreases chronic spontaneous seizures in a rat model of temporal lobe epilepsy. Brain 131:1506–1515.

https://doi.org/10.1093/BRAIN/AWN079

Bernard C (2012) Treating Epilepsy with a Light Potassium Diet. Sci Transl Med 4.

https://doi.org/10.1126/SCITRANSLMED.3005297

Wykes RC, Heeroma JH, Mantoan L, Zheng K, MacDonald DC, Deisseroth K, Hashemi KS, Walker MC, Schorge S, Kullmann DM (2012) Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy. Sci Transl Med 4:161ra152.

https://doi.org/10.1126/scitranslmed.3004190

Snowball A, Chabrol E, Wykes RC, Shekh-Ahmad T, Cornford JH, Lieb A, Hughes MP, Massaro G, Rahim AA, Hashemi KS, Kullmann DM, Walker MC, Schorge S (2019) Epilepsy Gene Therapy Using an Engineered Potassium Channel. J Neurosci 39:3159–3169.

https://doi.org/10.1523/JNEUROSCI.1143-18.2019

Nikitin ES, Balaban PM (2021) Diversity and Functional Features of Calcium-Dependent Potassium Channels as Determinants of Their Role in the Plasticity of Cerebral Neurons. Neurosci Behav Physiol 519 (51):1239–1243.

https://doi.org/10.1007/S11055-021-01186-Z

Trimmer JS (2015) Subcellular Localization of K+ Channels in Mammalian Brain Neurons: Remarkable Precision in the Midst of Extraordinary Complexity. Neuron 85:238–256.

https://doi.org/10.1016/j.neuron.2014.12.042

Bell TJ, Miyashiro KY, Sul J-Y, Buckley PT, Lee MT, McCullough R, Jochems J, Kim J, Cantor CR, Parsons TD, Eberwine JH (2010) Intron retention facilitates splice variant diversity in calcium-activated big potassium channel populations. Proc Natl Acad Sci U S A 107:21152–21157.

https://doi.org/10.1073/pnas.1015264107

Tian Y, Liao IH, Zhan X, Gunther JR, Ander BP, Liu D, Lit L, Jickling GC, Corbett BA, Bos-Veneman NGP, Hoekstra PJ, Sharp FR (2011) Exon expression and alternatively spliced genes in tourette syndrome. Am J Med Genet Part B Neuropsychiatr Genet 156:72–78.

https://doi.org/10.1002/ajmg.b.31140

Ghatta S, Nimmagadda D, Xu X, O’Rourke ST (2006) Large-conductance, calcium-activated potassium channels: structural and functional implications. Pharmacol Ther 110:103–116.

https://doi.org/10.1016/j.pharmthera.2005.10.007

Wallner M, Meera P, Toro L (1999) Molecular basis of fast inactivation in voltage and Ca 2+ -activated K + channels: A transmembrane β-subunit homolog. Proc Natl Acad Sci U S A 96:4137–4142. https://doi.org/10.1073/pnas.96.7.4137

Meera P, Wallner M, Toro L (2000) A neuronal β subunit (KCNMB4) makes the large conductance, voltage- and Ca 2+ -activated K + channel resistant to charybdotoxin and iberiotoxin. Proc Natl Acad SciU S A 97:5562–5567.

https://doi.org/10.1073/pnas.100118597

Xia X-M, Ding JP, Lingle CJ (1999) Molecular Basis for the Inactivation of Ca 2+ - and Voltage-Dependent BK Channels in Adrenal Chromaffin Cells and Rat Insulinoma Tumor Cells. J Neurosci 19:5255–5264.

https://doi.org/10.1523/JNEUROSCI.19-13-05255.1999

Köhler M, Hirschberg B, Bond CT, Kinzie JM, Marrion N V., Maylie J, Adelman JP (1996) Small-Conductance, Calcium-Activated Potassium Channels from Mammalian Brain. Science (80) 273:1709–1714.

https://doi.org/10.1126/science.273.5282.1709

King B, Rizwan AP, Asmara H, Heath NC, Engbers JDT, Dykstra S, Bartoletti TM, Hameed S, Zamponi GW, Turner RW (2015) IKCa Channels Are a Critical Determinant of the Slow AHP in CA1 Pyramidal Neurons. Cell Rep 11:175–182.

https://doi.org/10.1016/j.celrep.2015.03.026

Joiner WJ, Wang L-Y, Tang MD, Kaczmarek LK (1997) hSK4, a member of a novel subfamily of calcium-activated potassium channels. Proc Natl Acad Sci U S A 94:11013–11018.

https://doi.org/10.1073/pnas.94.20.11013

Higham J, Sahu G, Wazen R-M, Colarusso P, Gregorie A, Harvey BSJ, Goudswaard L, Varley G, Sheppard DN, Turner RW, Marrion N V. (2019) Preferred Formation of Heteromeric Channels between Coexpressed SK1 and IKCa Channel Subunits Provides a Unique Pharmacological Profile of Ca 2+ -Activated Potassium Channels. Mol Pharmacol 96:115–126.

https://doi.org/10.1124/mol.118.115634

Bean BP (2007) The action potential in mammalian central neurons. Nat Rev Neurosci 8:451–465. https://doi.org/10.1038/nrn2148

Roshchin MV, Ierusalimsky VN, Balaban PM, Nikitin ES (2020) Ca2+-activated KCa3.1 potassium channels contribute to the slow afterhyperpolarization in L5 neocortical pyramidal neurons. Sci Rep 10:14484.

https://doi.org/10.1038/s41598-020-71415-x

Nikitin E, Vinogradova L (2021) Potassium channels as prominent targets and tools for the treatment of epilepsy. Expert Opin Ther Targets 25:223–235.

https://doi.org/10.1080/14728222.2021.1908263

Miceli F, Soldovieri MV, Ambrosino P, Barrese V, Migliore M, Cilio MR, Taglialatela M (2013) Genotype–phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K v 7.2 potassium channel subunits. Proc Natl Acad Sci U S A 110:4386–4391.

https://doi.org/10.1073/pnas.1216867110

Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, Oliver KL, Mazarib A, Afawi Z, Korczyn A, Plazzi G, Petrou S, Berkovic SF, Scheffer IE, Dibbens LM (2012) Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 44:1188–1190.

https://doi.org/10.1038/ng.2440

Miller JP, Moldenhauer HJ, Keros S, Meredith AL (2021) An emerging spectrum of variants and clinical features in KCNMA1 -linked channelopathy. Channels 15:447–464.

https://doi.org/10.1080/19336950.2021.1938852

N’Gouemo P (2014) BK Ca channel dysfunction in neurological diseases. Front Physiol 5:373.

ttps://doi.org/10.3389/fphys.2014.00373

N’Gouemo P, Yasuda RP, Faingold CL (2009) Protein expression of small conductance calcium-activated potassium channels is altered in inferior colliculus neurons of the genetically epilepsy-prone rat. Brain Res 1270:107–111.

https://doi.org/10.1016/j.brainres.2009.02.034

Khandai P, Forcelli PA, N’Gouemo P (2020) Activation of small conductance calcium-activated potassium channels suppresses seizure susceptibility in the genetically epilepsy-prone rats. Neuropharmacology 163:107865.

https://doi.org/10.1016/j.neuropharm.2019.107865

Su T, Cong WD, Long YS, Luo AH, Sun WW, Deng WY, Liao WP (2008) Altered expression of voltage-gated potassium channel 4.2 and voltage-gated potassium channel 4-interacting protein, and changes in intracellular calcium levels following lithium-pilocarpine-induced status epilepticus. Neuroscience 157:566–576.

https://doi.org/10.1016/j.neuroscience.2008.09.027

Pacheco Otalora LF, Hernandez EF, Arshadmansab MF, Francisco S, Willis M, Ermolinsky B, Zarei M, Knaus H-G, Garrido-Sanabria ER (2008) Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy. Brain Res 1200:116–131.

https://doi.org/10.1016/j.brainres.2008.01.017

Shruti S, Clem RL, Barth AL (2008) A seizure-induced gain-of-function in BK channels is associated with elevated firing activity in neocortical pyramidal neurons. Neurobiol Dis 30:323–330.

https://doi.org/10.1016/j.nbd.2008.02.002

Leo A, Citraro R, Constanti A, De Sarro G, Russo E (2015) Are big potassium-type Ca 2+ -activated potassium channels a viable target for the treatment of epilepsy? Expert Opin Ther Targets 19:911–926.

https://doi.org/10.1517/14728222.2015.1026258

Oliveira MS, Skinner F, Arshadmansab MF, Garcia I, Mello CF, Knaus H-G, Ermolinsky BS, Otalora LFP, Garrido-Sanabria ER (2010) Altered expression and function of small-conductance (SK) Ca2+-activated K+ channels in pilocarpine-treated epileptic rats. Brain Res 1348:187–199.

https://doi.org/10.1016/j.brainres.2010.05.095

Tiwari MN, Mohan S, Biala Y, Yaari Y (2019) Protein Kinase A-Mediated Suppression of the Slow Afterhyperpolarizing KCa3.1 Current in Temporal Lobe Epilepsy. J Neurosci 39:9914–9926.

https://doi.org/10.1523/JNEUROSCI.1603-19.2019

Chavas J, Marty A (2003) Coexistence of Excitatory and Inhibitory GABA Synapses in the Cerebellar Interneuron Network. J Neurosci 23:2019–2031.

https://doi.org/10.1523/JNEUROSCI.23-06-02019.2003

Malyshev AY, Roshchin MV, Smirnova GR, Dolgikh DA, Balaban PM, Ostrovsky MA (2017) Chloride conducting light activated channel GtACR2 can produce both cessation of firing and generation of action potentials in cortical neurons in response to light. Neurosci Lett 640:76–80.

https://doi.org/10.1016/j.neulet.2017.01.026

Messier JE, Chen H, Cai Z-L, Xue M (2018) Targeting light-gated chloride channels to neuronal somatodendritic domain reduces their excitatory effect in the axon. Elife 7.

https://doi.org/10.7554/eLife.38506

Magloire V, Cornford J, Lieb A, Kullmann DM, Pavlov I (2019) KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition. Nat Commun 10:1225.

https://doi.org/10.1038/s41467-019-08933-4

Agostinho AS, Mietzsch M, Zangrandi L, Kmiec I, Mutti A, Kraus L, Fidzinski P, Schneider UC, Holtkamp M, Heilbronn R, Schwarzer C (2019) Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy. EMBO Mol Med 11:e9963.

https://doi.org/10.15252/emmm.201809963