RGD Reference Report - Characterization of specific allosteric effects of the Na+ channel β1 subunit on the Nav1.4 isoform. - Rat Genome Database

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Characterization of specific allosteric effects of the Na+ channel β1 subunit on the Nav1.4 isoform.

Authors: Sánchez-Solano, Alfredo  Islas, Angel A  Scior, Thomas  Paiz-Candia, Bertin  Millan-PerezPeña, Lourdes  Salinas-Stefanon, Eduardo M 
Citation: Sánchez-Solano A, etal., Eur Biophys J. 2017 Jul;46(5):485-494. doi: 10.1007/s00249-016-1193-3. Epub 2016 Dec 23.
RGD ID: 13825439
Pubmed: PMID:28012039   (View Abstract at PubMed)
DOI: DOI:10.1007/s00249-016-1193-3   (Journal Full-text)

The mechanism of inactivation of mammalian voltage-gated Na+ channels involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the β1 subunit. Navβ1 subunits constitute single-pass transmembrane proteins that form protein-protein associations with pore-forming α subunits to allosterically modulate the Na+ influx into the cell during the action potential of every excitable cell in vertebrates. Here, we explored the role of the intracellular IFM motif of rNav1.4 (skeletal muscle isoform of the rat Na+ channel) on the α-β1 functional interaction and showed for the first time that the modulation of β1 is independent of the IFM motif. We found that: (1) Nav1.4 channels that lack the IFM inactivation particle can undergo a "C-type-like inactivation" albeit in an ultraslow gating mode; (2) β1 can significantly accelerate the inactivation of Nav1.4 channels in the absence of the IFM motif. Previously, we identified two residues (T109 and N110) on the β1 subunit that disrupt the α-β1 allosteric modulation. We further characterized the electrophysiological effects of the double alanine substitution of these residues demonstrating that it decelerates inactivation and recovery from inactivation, abolishes the modulation of steady-state inactivation and induces a current rundown upon repetitive stimulation, thus causing a general loss of function. Our results contribute to delineating the process of the mammalian Na+ channel inactivation. These findings may be relevant to the design of pharmacological strategies, targeting β subunits to treat pathologies associated to Na+ current dysfunction.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Scn1bRatregulation of voltage-gated sodium channel activity involved_inIDA PMID:28012039UniProt 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Scn1bRatvoltage-gated sodium channel complex part_ofIDA PMID:28012039UniProt 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Scn1bRatsodium channel regulator activity enablesIDA PMID:28012039UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Scn1b  (sodium voltage-gated channel beta subunit 1)


Additional Information