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Splice variants of Na(V)1.7 sodium channels have distinct β subunit-dependent biophysical properties.

Farmer, C; Cox, JJ; Fletcher, EV; Woods, CG; Wood, JN; Schorge, S; (2012) Splice variants of Na(V)1.7 sodium channels have distinct β subunit-dependent biophysical properties. PLOS One , 7 (7) , Article e41750. 10.1371/journal.pone.0041750. Green open access

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Abstract

Genes encoding the α subunits of neuronal sodium channels have evolutionarily conserved sites of alternative splicing but no functional differences have been attributed to the splice variants. Here, using Na(V)1.7 as an exemplar, we show that the sodium channel isoforms are functionally distinct when co-expressed with β subunits. The gene, SCN9A, encodes the α subunit of the Na(V)1.7 channel, and contains both sites of alternative splicing that are highly conserved. In conditions where the intrinsic properties of the Na(V)1.7 splice variants were similar when expressed alone, co-expression of β1 subunits had different effects on channel availability that were determined by splicing at either site in the α subunit. While the identity of exon 5 determined the degree to which β1 subunits altered voltage-dependence of activation (P = 0.027), the length of exon 11 regulated how far β1 subunits depolarised voltage-dependence of inactivation (P = 0.00012). The results could have a significant impact on channel availability, for example with the long version of exon 11, the co-expression of β1 subunits could lead to nearly twice as large an increase in channel availability compared to channels containing the short version. Our data suggest that splicing can change the way that Na(V) channels interact with β subunits. Because splicing is conserved, its unexpected role in regulating the functional impact of β subunits may apply to multiple voltage-gated sodium channels, and the full repertoire of β subunit function may depend on splicing in α subunits.

Type: Article
Title: Splice variants of Na(V)1.7 sodium channels have distinct β subunit-dependent biophysical properties.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0041750
Publisher version: http://dx.doi.org/10.1371/journal.pone.0041750
Language: English
Additional information: © 2012 Farmer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. SS holds a University Research Fellowship from the Royal Society. This work was funded by the MRC (CF, JJC, JNW, SS), BBSRC (JJC, JNW), and Wellcome Trust (JJC, CGW, JNW, SS), and World University Program grant R31-2008-000-10103-0 (JNW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: Alternative Splicing, Biophysical Phenomena, Exons, HEK293 Cells, Humans, Ion Channel Gating, NAV1.7 Voltage-Gated Sodium Channel, Protein Subunits
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/1358304
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