REVIEW article
Front. Neurol.
Sec. Epilepsy
This article is part of the Research TopicGenotype-Phenotype Correlations, Genetic Mechanisms of Phenotypic Heterogeneity, Optimized Diagnosis and Targeted Therapies in Epilepsy and Neurodevelopmental DisordersView all 6 articles
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and Epilepsy: Genetics, Circuits, and Treatments
Provisionally accepted
- University of South China, Hengyang, China
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Epilepsy is a common chronic disorder of the central nervous system characterized by recurrent seizures arising from abnormal, hypersynchronous neuronal activity; its pathogenesis is complex and remains incompletely understood. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are a family of voltage-gated ion channels that mediate the hyperpolarization-activated cation current (Ih) and play key roles in regulating neuronal excitability, rhythmic activity, and synaptic transmission. Recent studies indicate that abnormal HCN channel expression, pathogenic genetic variants, or dysregulated protein interactions are closely linked to the onset and progression of epilepsy and may contribute to disease by destabilizing membrane-potential homeostasis, perturbing neurotransmitter balance, and disrupting network-level control of excitability. This review summarizes the structural and functional properties of HCN channels and focuses on their mechanistic roles in epileptogenesis, with the goal of informing clinical diagnosis and therapeutic development.
Keywords: circuits, Epilepsy, Genetic mechanisms, HCN channels, targeted therapies
Received: 12 Nov 2025; Accepted: 22 Dec 2025.
Copyright: © 2025 Cai, Liao, Hu, Li, Zhao, Jin, Wang and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Hongwei Wang
Yongjun Chen
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