Publication Date:
2008-11-14
Description:
Voltage-activated sodium (Na(v)) channels are crucial for the generation and propagation of nerve impulses, and as such are widely targeted by toxins and drugs. The four voltage sensors in Na(v) channels have distinct amino acid sequences, raising fundamental questions about their relative contributions to the function and pharmacology of the channel. Here we use four-fold symmetric voltage-activated potassium (K(v)) channels as reporters to examine the contributions of individual S3b-S4 paddle motifs within Na(v) channel voltage sensors to the kinetics of voltage sensor activation and to forming toxin receptors. Our results uncover binding sites for toxins from tarantula and scorpion venom on each of the four paddle motifs in Na(v) channels, and reveal how paddle-specific interactions can be used to reshape Na(v) channel activity. One paddle motif is unique in that it slows voltage sensor activation, and toxins selectively targeting this motif impede Na(v) channel inactivation. This reporter approach and the principles that emerge will be useful in developing new drugs for treating pain and Na(v) channelopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587061/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587061/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bosmans, Frank -- Martin-Eauclaire, Marie-France -- Swartz, Kenton J -- ZIA NS003017-03/Intramural NIH HHS/ -- England -- Nature. 2008 Nov 13;456(7219):202-8. doi: 10.1038/nature07473.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19005548" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Motifs
;
Animals
;
Ion Channel Gating/*drug effects
;
Models, Molecular
;
Mutagenesis
;
Potassium Channels, Voltage-Gated/genetics/metabolism
;
Protein Interaction Domains and Motifs/genetics/physiology
;
Rats
;
Recombinant Fusion Proteins/genetics/metabolism
;
Scorpion Venoms/pharmacology
;
Sodium Channels/genetics/*metabolism
;
Spider Venoms/pharmacology
;
Xenopus
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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