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
Anti-cancer chemotherapy is.usually associated withperipheral neurotoxicity,which may result in severe pain hypersensitivity.Our previous study verified that miR-30b mediated the up-regulation of voltage gated sodium ...Anti-cancer chemotherapy is.usually associated withperipheral neurotoxicity,which may result in severe pain hypersensitivity.Our previous study verified that miR-30b mediated the up-regulation of voltage gated sodium channel 1.6(Nav1.6)in the dorsal root ganglia(DRG)of rats with oxaliplatin(OXA)-induced neuropathic pain(OIPN).However,the mechanism of how miR-30b is changed remains elusive.In the current study,we found that the level of TET1 as well as the hydroxymethylation level in miR-30b promotor were significantly decreased in the L3-L5 DRG of OIPN mice.展开更多
Ganglion cells(RGCs) are the sole output neurons of the retinal circuity. Here, we investigated whether and how dopamine D2 receptors modulate the excitability of dissociated rat RGCs. Application of the selective D2 ...Ganglion cells(RGCs) are the sole output neurons of the retinal circuity. Here, we investigated whether and how dopamine D2 receptors modulate the excitability of dissociated rat RGCs. Application of the selective D2 receptor agonist quinpirole inhibited outward K^+ currents, which were mainly mediated by glybenclamide-and 4-aminopyridine-sensitive channels, but not the tetraethylammonium-sensitive channel. In addition,quinpirole selectively enhanced Nav1.6 voltage-gated Na^+ currents. The intracellular c AMP/protein kinase A,Ca^2+/calmodulin-dependent protein kinase Ⅱ, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathways were responsible for the effects of quinpirole on K^+ and Na^+ currents, while phospholipase C/protein kinase C signaling was not involved. Under current-clamp conditions, the number of action potentials evoked by positive current injection was increased by quinpirole. Our results suggest that D2 receptor activation increases RGC excitability by suppressing outward K+currents and enhancing Nav1.6 currents, which may affect retinal visual information processing.展开更多
Background:Voltage-gated sodium channels are the targets of many commonly used antiepileptic drugs.NaV1.6,encoded by Scn8a,increased in chronic mesial temporal epilepsy animal models and co-localized with Ankyrin-G,en...Background:Voltage-gated sodium channels are the targets of many commonly used antiepileptic drugs.NaV1.6,encoded by Scn8a,increased in chronic mesial temporal epilepsy animal models and co-localized with Ankyrin-G,encoded by Ank3.We hypothesized that inhibition of Ank3 transcription by siRNA decrease the expression of NaV1.6.Results:We characterized expression of the target genes in hippocampal neuron HT22 cells by Real time-PCR.The melt peak in the resolution curve of Scn1a,Scn8a and Ank3 were all unique.Ank3 transcription was interfered and the relative Ank3 mRNA levels of the three interfered groups compared to GAPDH were 0.89±0.13,0.52±0.07 and 0.26±0.05 while that of the negative control group was 1.01±0.08(P<0.05).When Ank3 transcription was inhibited by siRNA,the relative mRNA levels of Scn8a decreased in the three groups(0.91±0.09,0.33±0.06 and 0.25±0.05),compared to the negative control group(1.10±0.09).Tested by Western blotting,protein levels of ankyrinG and Nav1.6 decreased after ank3-siRNA.Ankyrin-G in negative control group,group1,group2 and group1+2 were 0.813±0.051,0.744±0.041,0.477±0.055 and 0.351±0.190 respectively(P<0.01)while Nav1.6 were 0.934±0.036,0.867±0.078,0.498±0.070 and 0.586±0.180(P<0.01).The quantity analysis of immunofluorescence showed significant decrease of ankyrin-G and Nav1.6(Student’s test,P=0.046 and 0.016 respectively).Conclusion:We therefore concluded that in HT22 cells the expression of Nav1.6 was down-regulated by Ank3 RNA interference.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.
文摘Anti-cancer chemotherapy is.usually associated withperipheral neurotoxicity,which may result in severe pain hypersensitivity.Our previous study verified that miR-30b mediated the up-regulation of voltage gated sodium channel 1.6(Nav1.6)in the dorsal root ganglia(DRG)of rats with oxaliplatin(OXA)-induced neuropathic pain(OIPN).However,the mechanism of how miR-30b is changed remains elusive.In the current study,we found that the level of TET1 as well as the hydroxymethylation level in miR-30b promotor were significantly decreased in the L3-L5 DRG of OIPN mice.
基金the National Natural Science Foundation of China(31671078,81790642,and 31872765)the Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)and ZJ Lab.
文摘Ganglion cells(RGCs) are the sole output neurons of the retinal circuity. Here, we investigated whether and how dopamine D2 receptors modulate the excitability of dissociated rat RGCs. Application of the selective D2 receptor agonist quinpirole inhibited outward K^+ currents, which were mainly mediated by glybenclamide-and 4-aminopyridine-sensitive channels, but not the tetraethylammonium-sensitive channel. In addition,quinpirole selectively enhanced Nav1.6 voltage-gated Na^+ currents. The intracellular c AMP/protein kinase A,Ca^2+/calmodulin-dependent protein kinase Ⅱ, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathways were responsible for the effects of quinpirole on K^+ and Na^+ currents, while phospholipase C/protein kinase C signaling was not involved. Under current-clamp conditions, the number of action potentials evoked by positive current injection was increased by quinpirole. Our results suggest that D2 receptor activation increases RGC excitability by suppressing outward K+currents and enhancing Nav1.6 currents, which may affect retinal visual information processing.
基金the National Nature Science foundation(81000554)Guangdong Nature Science foundation(2018A030313345)the Science and Technology Foundation of Guangdong Province(2008B030301058).
文摘Background:Voltage-gated sodium channels are the targets of many commonly used antiepileptic drugs.NaV1.6,encoded by Scn8a,increased in chronic mesial temporal epilepsy animal models and co-localized with Ankyrin-G,encoded by Ank3.We hypothesized that inhibition of Ank3 transcription by siRNA decrease the expression of NaV1.6.Results:We characterized expression of the target genes in hippocampal neuron HT22 cells by Real time-PCR.The melt peak in the resolution curve of Scn1a,Scn8a and Ank3 were all unique.Ank3 transcription was interfered and the relative Ank3 mRNA levels of the three interfered groups compared to GAPDH were 0.89±0.13,0.52±0.07 and 0.26±0.05 while that of the negative control group was 1.01±0.08(P<0.05).When Ank3 transcription was inhibited by siRNA,the relative mRNA levels of Scn8a decreased in the three groups(0.91±0.09,0.33±0.06 and 0.25±0.05),compared to the negative control group(1.10±0.09).Tested by Western blotting,protein levels of ankyrinG and Nav1.6 decreased after ank3-siRNA.Ankyrin-G in negative control group,group1,group2 and group1+2 were 0.813±0.051,0.744±0.041,0.477±0.055 and 0.351±0.190 respectively(P<0.01)while Nav1.6 were 0.934±0.036,0.867±0.078,0.498±0.070 and 0.586±0.180(P<0.01).The quantity analysis of immunofluorescence showed significant decrease of ankyrin-G and Nav1.6(Student’s test,P=0.046 and 0.016 respectively).Conclusion:We therefore concluded that in HT22 cells the expression of Nav1.6 was down-regulated by Ank3 RNA interference.
