中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (6): 2085-2106.doi: 10.4103/NRR.NRR-D-25-00260

• 综述:神经损伤修复保护与再生 •    下一篇

神经系统中的电压门控钠通道:从分子生理学到治疗干预

  

  • 出版日期:2026-06-15 发布日期:2025-09-16
  • 基金资助:
    国家自然科学基金(82471107、31970930);国家重点研究与发展计划项目(2024YFA1108701);湖北省自然科学基金(2020CFA069、2018CFB434、2025AFB042);武汉科技大学神经科学团队建设项目(1180002、1180030)。

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).

摘要:

电压门控钠通道是神经系统中重要的离子传导途径,在调节神经元兴奋性和信号转导方面发挥着不可替代的作用。这篇综述全面分析了电压门控钠通道的分子机制和病理生理学意义,尤其侧重于阐明不同亚型(包括Nav1.1、Nav1.2和Nav1.6)在家族性偏瘫性偏头痛、癫痫、自闭症谱系障碍和视网膜功能障碍等各种神经系统疾病中的分子作用机制。文章的目的是全面了解电压门控钠通道的发病机制,系统地探讨治疗策略从传统方法到创新方法的演变路径。首先,文章详细分析了两大类传统钠通道阻滞剂及其应用:抗癫痫药物(如卡马西平、拉莫三嗪和苯妥英)和抗心律失常药物(如利多卡因、非卡因和奎尼丁)。然而,这些传统的阻断剂由于缺乏选择性而存在局限性,促使研究向更精确的治疗方向发展。其次,文章探讨了具有不同作用机制的药物,包括加巴喷丁、大麻二酚和钙通道阻滞剂。这些药物从多个角度共同调节神经元的兴奋性,为缓解症状提供了多种选择。再次,在创新疗法方面,这篇综述重点介绍了针对特定疾病的基因疗法的进展,如 STK-001(促进 SCN1A 基因的有效剪接)和 ETX101(利用 AAV9 载体传递工程化转录因子),这两种疗法都提供了针对德雷维综合征的靶向治疗方案。最后,文章还总结了正在进行临床试验的各种创新疗法,包括已获得美国食品药品管理局孤儿药认定的PRAX-222(治疗SCN2A功能增益突变相关癫痫)和选择性Nav1.6抑制剂NBI-921352(治疗SCN8A相关癫痫)。文章通过对神经系统中的电压门控钠通道传统药物和基因治疗优缺点的综合比较,展望未来的治疗策略将综合两种方法的优势,向个性化精准医疗方向迈进,以期为离子通道疾病患者提供更精准有效的治疗方案。

https://orcid.org/0000-0002-1785-1114 (Huan Qin); https://orcid.org/0000-0002-8122-430X (Kai Yao)

关键词: 自闭症谱系障碍, 通道病, 临床试验, 德雷维综合征, 癫痫, 家族性偏瘫偏头痛, 基因治疗, 神经元再生, 肾素-血管紧张素系统, 视网膜变性

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