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Alkanols inhibit voltage-gated K+ channels via a distinct gating modifying mechanism that prevents gate opening

Alkanols inhibit voltage-gated K+ channels via a distinct gating modifying mechanism that prevents gate opening

Authors :
Evelyn Martinez-Morales
Ivan Kopljar
Alain J. Labro
Dirk J. Snyders
Source :
SCIENTIFIC REPORTS, Scientific Reports, Scientific reports
Publication Year :
2015
Publisher :
Nature Publishing Group, 2015.

Abstract

Alkanols are small aliphatic compounds that inhibit voltage-gated K+ (Kv) channels through a yet unresolved gating mechanism. Kv channels detect changes in the membrane potential with their voltage-sensing domains (VSDs) that reorient and generate a transient gating current. Both 1-Butanol (1-BuOH) and 1-Hexanol (1-HeOH) inhibited the ionic currents of the Shaker Kv channel in a concentration dependent manner with an IC50 value of approximately 50 mM and 3 mM, respectively. Using the non-conducting Shaker-W434F mutant, we found that both alkanols immobilized approximately 10% of the gating charge and accelerated the deactivating gating currents simultaneously with ionic current inhibition. Thus, alkanols prevent the final VSD movement(s) that is associated with channel gate opening. Applying 1-BuOH and 1-HeOH to the Shaker-P475A mutant, in which the final gating transition is isolated from earlier VSD movements, strengthened that neither alkanol affected the early VSD movements. Drug competition experiments showed that alkanols do not share the binding site of 4-aminopyridine, a drug that exerts a similar effect at the gating current level. Thus, alkanols inhibit Shaker-type Kv channels via a unique gating modifying mechanism that stabilizes the channel in its non-conducting activated state.

Details

Language :
English
ISSN :
20452322
Database :
OpenAIRE
Journal :
Scientific Reports
Accession number :
edsair.doi.dedup.....47a23a9e01e776ebd572322dc1148684
Full Text :
https://doi.org/10.1038/srep17402