{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:46:07Z","timestamp":1787071567365,"version":"build-2736575974"},"reference-count":133,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:p>\n                    The voltage-gated sodium channel Nav1.6, encoded by the sodium voltage-gated channel alpha subunit 8 gene, is a crucial regulator of neuronal excitability, with widespread expression throughout the central and peripheral nervous systems. Recent breakthroughs in structural biology, particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm, have provided unprecedented insights into its molecular organization and functional modulation. As a key mediator of action potential initiation and propagation, Nav1.6 possesses unique biophysical properties, including persistent and resurgent sodium currents that critically influence neuronal firing patterns. This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions. Key findings include the following: (1) Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype\u2013phenotype correlations, where gain-of-function variants lead to severe epileptic encephalopathies, while loss-of-function variants are associated with generalized epilepsy, highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967. (2) In Alzheimer\u2019s disease, Nav1.6 mediates amyloid-\u03b2 oligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling, suggesting novel disease-modifying strategies. (3) Parkinson\u2019s disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization. (4) Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration, with riluzole showing partial efficacy through sodium current modulation. (5) Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons, which drives calcium-dependent axonal injury via reverse Na\n                    <jats:sup>+<\/jats:sup>\n                    \/Ca\n                    <jats:sup>2+<\/jats:sup>\n                    exchange. (6) Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons, regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-\u03b1 signaling pathways. (7) Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability. Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches, including state-dependent pore blockers designed using structural insights; allosteric modulators targeting specific conformations; gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides; and miRNA-based regulation of channel expression. Current challenges include achieving sufficient subtype selectivity, optimizing blood\u2013brain barrier penetration, and developing clinically relevant biomarkers for patient stratification. Future directions emphasize the integration of advanced technologies\u2014such as single-cell multiomics to map neuronal subtype-specific expression patterns, patient-derived organoids for personalized drug testing, and machine learning-assisted drug design\u2014to accelerate translation. Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.\n                  <\/jats:p>","DOI":"10.4103\/nrr.nrr-d-25-00354","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T10:00:16Z","timestamp":1759140016000},"page":"3352-3362","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":1,"title":["Structure and function of voltage-gated sodium channel Nav1.6: Involvement in the pathological process of neural injury"],"prefix":"10.4103","volume":"21","author":[{"given":"Huaiyuan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaowu","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2914-0249","authenticated-orcid":false,"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"R1-20260430","doi-asserted-by":"crossref","first-page":"600050","DOI":"10.3389\/fneur.2021.600050","article-title":"Voltage gated sodium channel genes in epilepsy: mutations, functional studies, and treatment dimensions","volume":"12","author":"Ademuwagun","year":"2021","journal-title":"Front Neurol"},{"key":"R2-20260430","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3892\/ijmm.2023.5249","article-title":"Role of the voltage-gated sodium channel Nav1.6 in glioma and candidate drugs screening","volume":"51","author":"Ai","year":"2023","journal-title":"Int J Mol Med"},{"key":"R3-20260430","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1111\/epi.14196","article-title":"The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy","volume":"59","author":"Baker","year":"2018","journal-title":"Epilepsia"},{"key":"R4-20260430","first-page":"1191","article-title":"Voltage-gated sodium channel dysfunctions in neurological disorders","volume":"13","author":"Barbieri","year":"2023","journal-title":"Life (Basel)"},{"key":"R5-20260430","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12990-015-0063-9","article-title":"Navbeta4 regulates fast resurgent sodium currents and excitability in sensory neurons","volume":"11","author":"Barbosa","year":"2015","journal-title":"Mol Pain"},{"key":"R6-20260430","first-page":"1191","article-title":"Voltage-Gated Na (+) Channels in Alzheimer\u2019s disease: physiological roles and therapeutic potential","volume":"13","author":"Baumgartner","year":"2023","journal-title":"Life (Basel)"},{"key":"R7-20260430","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1111\/epi.14557","article-title":"Progress report on new antiepileptic drugs: a summary of the fourteenth eilat conference on new antiepileptic drugs and devices (EILAT XIV). 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