Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (6): 2085-2106.doi: 10.4103/NRR.NRR-D-25-00260

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Voltage-gated sodium channels in the nervous system: Molecular physiology to therapeutic interventions

Ni Li1, 2, Lin Yan1, 2, Anna Peng1, 2, Xuefei Fu1, 2, Huan Qin1, 2, *, Kai Yao1, 2, *   

  1. 1 Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, Hubei Province, China;  2 College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, Hubei Province, China
  • Online:2026-06-15 Published:2025-09-16
  • Contact: Huan Qin, PhD, QHainne2021@outlook.com; Kai Yao, PhD, kyao21@outlook.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82471107, 31970930 (both to KY); the National Key Research and Development Program of China, No. 2024YFA1108701 (to KY); the Natural Science Foundation of Hubei Province, Nos. 2020CFA069 (to KY), 2018CFB434 (to KY), 2025AFB042 (to HQ); the Neuroscience Team Development Project of Wuhan University of Science and Technology, Nos. 1180002, 1180030 (both to KY).

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Abstract:

Voltage-gated sodium channels are essential ionic-conductance pathways in the nervous system, which play an irreplaceable role in modulating neuronal excitability and signal transduction. This review comprehensively analyzes the molecular mechanisms and pathophysiological significance of voltage-gated sodium channels, with particular emphasis on elucidating the molecular-action mechanisms of the distinct subtypes of these channels, including Nav1.1, Nav1.2, and Nav1.6, across various neurological disorders such as familial hemiplegic migraine, epilepsy, autism spectrum disorder, and retinal dysfunction. This review also provides a comprehensive overview of the pathogenic mechanisms associated with voltage-gated sodium channels, and systematically clarifies the evolutionary pathway of treatment strategies from conventional to innovative approaches. It analyzes two major categories of conventional sodium channel blockers and their applications: antiepileptic drugs (such as carbamazepine, lamotrigine, and phenytoin) and antiarrhythmic drugs (such as lidocaine, flecainide, and quinidine). However, these conventional blockers show limitations because of the lack of selectivity, driving research toward more precise therapeutic directions. Additionally, this review evaluates gabapentin, cannabidiol, and calcium channel blockers with different mechanisms of action. These drugs modulate neuronal excitability from multiple perspectives, providing diverse options for symptom relief. This review also highlights advances in gene therapy for specific diseases, such as STK-001, which promotes effective splicing of the SCN1A gene, and ETX101, which utilizes adeno-associated virus 9 vectors to deliver engineered transcription factors. These two agents provide targeted therapeutic solutions for Dravet syndrome. Furthermore, this review summarizes some innovative therapeutic agents in clinical trials, including PRAX-222 (for SCN2A gain-of-function mutation-related epilepsy), which has received Food and Drug Administration orphan drug designation, and the selective Nav1.6 inhibitor NBI-921352 (for SCN8A-related epilepsy). Collectively, this review comprehensively compares the advantages and disadvantages of conventional drugs and gene therapy and envisions future treatment strategies that integrate the strengths of both approaches, facilitating personalized precision medicine to provide more accurate and effective treatment options for patients with ion channel diseases.

Key words: autism spectrum disorder, channelopathies, clinical trial, Dravet syndrome, epilepsy, familial hemiplegic migraine, gene therapy, nerve regeneration, neuronal regeneration, reninangiotensin system, retinal degeneration