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...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-phenotype 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’s disease,Nav1.6 mediates amyloid-βoligomer-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’s 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+/Ca2+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-αsignaling 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-brain barrier penetration,and developing clinically relevant biomarkers for patient stratification.Future directions emphasize the integration of advanced technologies-such as single-cell multiomics to map neuronal subtype-specific expression patterns,patient-derived organoids for personalized drug testing,and machine learning-assisted drug design-to accelerate translation.Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.展开更多
BACKGROUND Voltage-gated sodium channels(VGSCs,or Navs)are highly expressed in various tumors and play a critical role in tumor metastasis and invasion.AIM To identify Nav1.6-associated cancer genes through bioinforma...BACKGROUND Voltage-gated sodium channels(VGSCs,or Navs)are highly expressed in various tumors and play a critical role in tumor metastasis and invasion.AIM To identify Nav1.6-associated cancer genes through bioinformatics analysis and experimental validation,with the goal of determining the role of Nav1.6 in colorectal cancer(CRC)metastasis.METHODS The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)data were analyzed using weighted correlation network analysis(WGCNA)and Venn analysis to identify Nav1.6-associated genes in CRC.siRNA,real-time PCR,and western blotting were employed to validate the Nav1.6-associated cancer genes and signaling pathways identified in CRC.Cell counting kit-8 and Transwell migration assays were used to assess the proliferation and migration of CRC cells.RESULTS The analysis of TCGA and GEO datasets,along with WGCNA,identified 575 differentially expressed genes associated with SCN8A(Nav1.6)in CRC,which were particularly enriched in MAPK signaling pathways.Tissue microarray analysis of surgical samples revealed elevated Nav1.6 levels in CRC tissues,which were predominantly in the cytoplasm and nucleus rather than in the membrane.Cytoplasmic Nav1.6 expression increased with T stage increases,consistent with the TCGA findings.SCN8A knockdown in colon tumor cells significantly reduced cell proliferation and invasion and downregulated key proteins in the RAF-MAPK pathway.CONCLUSION These findings suggest that Nav1.6 promotes CRC cell proliferation and invasion which is related to the MAPK signaling pathway.展开更多
基金supported by the Science and Technology Program Joint Program(Applied Basic Research Project)of Liaoning Province,China,No.2023JH2/101700079(to JunW).
文摘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-phenotype 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’s disease,Nav1.6 mediates amyloid-βoligomer-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’s 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+/Ca2+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-αsignaling 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-brain barrier penetration,and developing clinically relevant biomarkers for patient stratification.Future directions emphasize the integration of advanced technologies-such as single-cell multiomics to map neuronal subtype-specific expression patterns,patient-derived organoids for personalized drug testing,and machine learning-assisted drug design-to accelerate translation.Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.
基金Supported by Science and Technology Project of Quzhou of China,No.2021Y011Beijing Science and Technology Innovation Medical Development Foundation,No.KC2021-JX-0186-81.
文摘BACKGROUND Voltage-gated sodium channels(VGSCs,or Navs)are highly expressed in various tumors and play a critical role in tumor metastasis and invasion.AIM To identify Nav1.6-associated cancer genes through bioinformatics analysis and experimental validation,with the goal of determining the role of Nav1.6 in colorectal cancer(CRC)metastasis.METHODS The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)data were analyzed using weighted correlation network analysis(WGCNA)and Venn analysis to identify Nav1.6-associated genes in CRC.siRNA,real-time PCR,and western blotting were employed to validate the Nav1.6-associated cancer genes and signaling pathways identified in CRC.Cell counting kit-8 and Transwell migration assays were used to assess the proliferation and migration of CRC cells.RESULTS The analysis of TCGA and GEO datasets,along with WGCNA,identified 575 differentially expressed genes associated with SCN8A(Nav1.6)in CRC,which were particularly enriched in MAPK signaling pathways.Tissue microarray analysis of surgical samples revealed elevated Nav1.6 levels in CRC tissues,which were predominantly in the cytoplasm and nucleus rather than in the membrane.Cytoplasmic Nav1.6 expression increased with T stage increases,consistent with the TCGA findings.SCN8A knockdown in colon tumor cells significantly reduced cell proliferation and invasion and downregulated key proteins in the RAF-MAPK pathway.CONCLUSION These findings suggest that Nav1.6 promotes CRC cell proliferation and invasion which is related to the MAPK signaling pathway.
