ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2009
The ataxia3 mutation in the N-terminal cytoplasmic domain of sodium channel Na(v)1.6 disrupts intracellular trafficking.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 45 citations in OpenAlex.
- Direct fluorescent labeling of NF186 and NaV1.6 in living primary neurons using bioorthogonal click chemistry.Journal of cell science · 2023Article
- Review
- Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites.Nature communications · 2021Article
- Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions.Frontiers in neurology · 2021Review
- Trafficking mechanisms underlying NaChannels (Austin, Tex.) · 2020Review
- Inter-Regulation of KInternational journal of molecular sciences · 2020Article
- Case studies in neuroscience: a novel amino acid duplication in the NHJournal of neurophysiology · 2019Article
- The MAP1B Binding Domain of NaThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Article
- Single-Molecule Imaging of Nav1.6 on the Surface of Hippocampal Neurons Reveals Somatic Nanoclusters.Biophysical journal · 2016Article
- Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol.Brain : a journal of neurology · 2016Article
- Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder.Neurobiology of disease · 2016Article
- Characterization of Endogenous Sodium Channels in the ND7-23 Neuroblastoma Cell Line: Implications for Use as a Heterologous Ion Channel Expression System Suitable for Automated Patch Clamp Screening.Assay and drug development technologies · 2016Article
- Amyloid precursor protein enhances Nav1.6 sodium channel cell surface expression.The Journal of biological chemistry · 2015Article
- Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy.Human molecular genetics · 2015Article
- Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy.Epilepsy research · 2014Article
- A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy.Neurobiology of disease · 2014Article
- Sodium channel SCN8A (Nav1.6): properties and de novo mutations in epileptic encephalopathy and intellectual disability.Frontiers in genetics · 2013Review
- A computational kinetic model of diffusion for molecular systems.The Journal of chemical physics · 2013Article
- Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice.The Journal of physiology · 2013Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
The ENU-induced neurological mutant ataxia3 was mapped to distal mouse chromosome 15. Sequencing of the positional candidate gene Scn8a encoding the sodium channel Na(v)1.6 identified a T>C transition in exon 1 resulting in the amino acid substitution p.S21P near the N terminus of the channel. The cytoplasmic N-terminal region is evolutionarily conserved but its function has not been well characterized. ataxia3 homozygotes exhibit a severe disorder that includes ataxia, tremor, and juvenile lethality. Unlike Scn8a null mice, they retain partial hindlimb function. The mutant transcript is stable but protein abundance is reduced and the mutant channel is not detected in its usual site of concentration at nodes of Ranvier. In whole-cell patch-clamp studies of transfected ND7/23 cells that were maintained at 37 degrees C, the mutant channel did not produce sodium current, and function was not restored by coexpression of beta1 and beta2 subunits. However, when transfected cells were maintained at 30 degrees C, the mutant channel generated voltage-dependent inward sodium currents with an average peak current density comparable with wild type, demonstrating recovery of channel activity. Immunohistochemistry of primary cerebellar granule cells from ataxia3 mice demonstrated that the mutant protein is retained in the cis-Golgi. This trafficking defect can account for the low level of Na(v)1.6-S21P at nodes of Ranvier in vivo and at the surface of transfected cells. The data demonstrate that the cytoplasmic N-terminal domain of the sodium channel is required for anterograde transport from the Golgi complex to the plasma membrane.
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