Modulation of Nav1.5 channel function by an alternatively spliced sequence in the DII/DIII linker region.

Details

Serval ID
serval:BIB_7DAEDC15FEB7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Modulation of Nav1.5 channel function by an alternatively spliced sequence in the DII/DIII linker region.
Journal
Journal of Biological Chemistry
Author(s)
Camacho J.A., Hensellek S., Rougier J.S., Blechschmidt S., Abriel H., Benndorf K., Zimmer T.
ISSN
0021-9258
Publication state
Published
Issued date
2006
Peer-reviewed
Oui
Volume
281
Number
14
Pages
9498-9506
Language
english
Notes
Publication types: Journal Article
Abstract
In the present study, we identified a novel splice variant of the human cardiac Na(+) channel Na(v)1.5 (Na(v)1.5d), in which a 40-amino acid sequence of the DII/DIII intracellular linker is missing due to a partial deletion of exon 17. Expression of Na(v)1.5d occurred in embryonic and adult hearts of either sex, indicating that the respective alternative splicing is neither age-dependent nor gender-specific. In contrast, Na(v)1.5d was not detected in the mouse heart, indicating that alternative splicing of Na(v)1.5 is species-dependent. In HEK293 cells, splice variant Na(v)1.5d generated voltage-dependent Na(+) currents that were markedly reduced compared with wild-type Na(v)1.5. Experiments with mexiletine and 8-bromo-cyclic AMP suggested that the trafficking of Na(v)1.5d channels was not impaired. However, single-channel recordings showed that the whole-cell current reduction was largely due to a significantly reduced open probability. Additionally, steady-state activation and inactivation were shifted to depolarized potentials by 15.9 and 5.1 mV, respectively. Systematic mutagenesis analysis of the spliced region provided evidence that a short amphiphilic region in the DII/DIII linker resembling an S4 voltage sensor of voltage-gated ion channels is an important determinant of Na(v)1.5 channel gating. Moreover, the present study identified novel short sequence motifs within this amphiphilic region that specifically affect the voltage dependence of steady-state activation and inactivation and current amplitude of human Na(v)1.5.
Keywords
Adult, Age Factors, Aged, Alternative Splicing, Amino Acid Sequence, Electrophysiology, Embryo, Mammalian, Exons, Female, Frameshift Mutation, Gene Expression Profiling, Heart/physiology, Humans, Ion Channel Gating, Male, Middle Aged, Molecular Sequence Data, Muscle Proteins/physiology, Mutagenesis, Site-Directed, RNA, Sex Factors, Sodium Channels/physiology
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 10:56
Last modification date
20/08/2019 14:38
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