Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Overview

Journal Pharmacol Rev

Specialty Pharmacology

Date 2017 Dec 22

PMID 29263209

Citations 117

Authors

Julia Oyrer

Snezana Maljevic

Ingrid E Scheffer

Samuel F Berkovic

Steven Petrou

Christopher A Reid

Affiliations

Soon will be listed here.

Abstract

Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact of these genetic discoveries is wide reaching-from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies.

Citing Articles

Transcriptomic analyses of human brains with Alzheimer's disease identified dysregulated epilepsy-causing genes.

Eteleeb A, Alves S, Buss S, Shafi M, Press D, Garcia-Cairasco N medRxiv. 2025; .

PMID: 39974070 PMC: 11838929. DOI: 10.1101/2025.01.02.25319900.

Advancements in Surgical Therapies for Drug-Resistant Epilepsy: A Paradigm Shift towards Precision Care.

Zhong C, Yang K, Wang N, Yang L, Yang Z, Xu L Neurol Ther. 2025; 14(2):467-490.

PMID: 39928287 PMC: 11906941. DOI: 10.1007/s40120-025-00710-4.

Identification and verification of autophagy-related gene signatures and their association with immune infiltration and drug responsiveness in epilepsy.

He H, Zhang X, Chen F Front Neurol. 2025; 15:1503632.

PMID: 39911741 PMC: 11794110. DOI: 10.3389/fneur.2024.1503632.

Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits and Absence-Like Seizures in a Gene-Trap Haploinsufficiency Mouse Model.

Ma K, McDaniel K, Zhang D, Webb M, Qin L Genes (Basel). 2025; 15(12.

PMID: 39766886 PMC: 11675260. DOI: 10.3390/genes15121619.

Cannabichromene from full-spectrum hemp extract exerts acute anti-seizure effects through allosteric activation of GABA receptors.

Wang Z, Zheng H, Yang H, Song H, Lian J, Peng C Fundam Res. 2024; 4(6):1357-1364.

PMID: 39734535 PMC: 11670702. DOI: 10.1016/j.fmre.2023.05.023.

References

Caddick S, Wang C, Fletcher C, Jenkins N, Copeland N, Hosford D . Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4(lh)) and tottering (Cacna1atg) mouse thalami. J Neurophysiol. 1999; 81(5):2066-74. DOI: 10.1152/jn.1999.81.5.2066. View

Zuberi S, Eunson L, Spauschus A, De Silva R, Tolmie J, Wood N . A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain. 1999; 122 ( Pt 5):817-25. DOI: 10.1093/brain/122.5.817. View

Lerche H, Biervert C, Alekov A, Schleithoff L, Lindner M, Klinger W . A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions. Ann Neurol. 1999; 46(3):305-12. DOI: 10.1002/1531-8249(199909)46:3<305::aid-ana5>3.0.co;2-5. View

Hirose S, Iwata H, Akiyoshi H, Kobayashi K, Ito M, Wada K . A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 1999; 53(8):1749-53. DOI: 10.1212/wnl.53.8.1749. View

Jun K, Piedras-Renteria E, Smith S, Wheeler D, Lee S, Lee T . Ablation of P/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(1A)-subunit. Proc Natl Acad Sci U S A. 1999; 96(26):15245-50. PMC: 24805. DOI: 10.1073/pnas.96.26.15245. View

Rundfeldt C, Netzer R . The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits. Neurosci Lett. 2000; 282(1-2):73-6. DOI: 10.1016/s0304-3940(00)00866-1. View

Caldwell J, Schaller K, Lasher R, Peles E, Levinson S . Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc Natl Acad Sci U S A. 2000; 97(10):5616-20. PMC: 25877. DOI: 10.1073/pnas.090034797. View

Johannessen C . Mechanisms of action of valproate: a commentatory. Neurochem Int. 2000; 37(2-3):103-10. DOI: 10.1016/s0197-0186(00)00013-9. View

Planells-Cases R, Caprini M, Zhang J, Rockenstein E, Rivera R, Murre C . Neuronal death and perinatal lethality in voltage-gated sodium channel alpha(II)-deficient mice. Biophys J. 2000; 78(6):2878-91. PMC: 1300874. DOI: 10.1016/S0006-3495(00)76829-9. View

10.

Watanabe Y, Kimura J . Inhibitory effect of amiodarone on Na(+)/Ca(2+) exchange current in guinea-pig cardiac myocytes. Br J Pharmacol. 2000; 131(1):80-4. PMC: 1572287. DOI: 10.1038/sj.bjp.0703527. View

11.

Eunson L, Rea R, Zuberi S, Youroukos S, Panayiotopoulos C, Liguori R . Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability. Ann Neurol. 2000; 48(4):647-56. View

12.

Catterall W . Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol. 2000; 16:521-55. DOI: 10.1146/annurev.cellbio.16.1.521. View

13.

De Fusco M, Becchetti A, Patrignani A, Annesi G, Gambardella A, Quattrone A . The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet. 2000; 26(3):275-6. DOI: 10.1038/81566. View

14.

Phillips H, Favre I, Kirkpatrick M, Zuberi S, Goudie D, Heron S . CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. Am J Hum Genet. 2000; 68(1):225-31. PMC: 1234917. DOI: 10.1086/316946. View

15.

Wilmshurst J, Appleton D, Grattan-Smith P . Migrating partial seizures in infancy: two new cases. J Child Neurol. 2000; 15(11):717-22. DOI: 10.1177/088307380001501102. View

16.

Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G . GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience. 2000; 101(4):815-50. DOI: 10.1016/s0306-4522(00)00442-5. View

17.

Shieh C, Coghlan M, Sullivan J, Gopalakrishnan M . Potassium channels: molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev. 2000; 52(4):557-94. View

18.

Kearney J, Plummer N, Smith M, Kapur J, Cummins T, Waxman S . A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neuroscience. 2001; 102(2):307-17. DOI: 10.1016/s0306-4522(00)00479-6. View

19.

Dani J . Overview of nicotinic receptors and their roles in the central nervous system. Biol Psychiatry. 2001; 49(3):166-74. DOI: 10.1016/s0006-3223(00)01011-8. View

20.

Chen K, Aradi I, Thon N, Baram T, Soltesz I . Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability. Nat Med. 2001; 7(3):331-7. PMC: 3382967. DOI: 10.1038/85480. View