Voltage-Gated Ion Channels in Epilepsy and Neuroexcitability Disorders

Voltage-gated ion channels are the molecular gatekeepers of neuronal excitability. By precisely controlling the flow of sodium, potassium, calcium, and chloride ions across the membrane, they shape action potential generation, propagation, and termination in individual neurons and across large-scale brain networks. When their function is disrupted — through pathogenic mutations, altered expression, or post-translational dysregulation — the result is a shift toward hyperexcitability that can manifest as epilepsy or other neuroexcitability disorders.The past two decades have dramatically accelerated our understanding of the genetic architecture of epileptic channelopathies. Loss-of-function mutations in SCN1A (Nav1.1) underlie Dravet syndrome; gain-of-function variants in KCNT1, KCNQ2, and KCNQ3 drive neonatal epileptic encephalopathies; mutations in CACNA1A and SCN8A produce a spectrum of pharmacoresistant phenotypes. Yet despite this explosion of genotype–phenotype knowledge, translating mechanistic insight into effective, precision-targeted pharmacological interventions remains a major challenge. Many patients with genetic epilepsies fail to respond to available antiseizure medications — or are paradoxically worsened by them — underscoring the need for channel-specific therapeutic strategies.This Research Topic invites original research articles, reviews, systematic reviews, and clinical studies that advance our understanding of how voltage-gated ion channels contribute to epilepsy and related neuroexcitability disorders, and how they can be pharmacologically targeted. We particularly welcome contributions addressing:Channelopathy mechanisms — biophysical and structural characterization of epilepsy-causing mutations in Nav, Kv, Cav, and ClC channel familiesPrecision pharmacology — small-molecule modulators, toxin-derived peptides, and allosteric strategies that selectively target pathological channel statesAntiseizure drug mechanisms and resistance — molecular determinants of drug efficacy and pharmacoresistance in both genetic and acquired epilepsiesEmerging targets — HCN channels, two-pore-domain potassium channels (K2P), and accessory subunits as novel pharmacological entry pointsNovel therapeutic modalities — gene therapy, RNA-based approaches, and optogenetics as channel-targeting strategiesTranslational and clinical studies — iPSC-derived neuronal models, patient-derived data, biomarkers of channel dysfunction, and precision medicine outcomesNetwork-level pharmacology — how channel-targeted drugs reshape excitation–inhibition balance and network dynamics in vivoBy bringing together experts in ion channel biophysics, medicinal chemistry, neuropharmacology, genetics, and clinical epileptology, this Research Topic aims to build a comprehensive, cross-disciplinary resource that advances both mechanistic understanding and the development of next-generation therapies for epilepsy and neuroexcitability disorders. Topic editors: Claudia Duranti, Atul Daiwile, Sandesh Kamdi, Edward Glasscock Source: https://www.frontiersin.org/research-topics/86610/voltage-gated-ion-channels-in-epilepsy-and-neuroexcitability-disorders