Title
Alkanols inhibit voltage-gated <tex>$K^{+}$</tex> channels via a distinct gating modifying mechanism that prevents gate opening Alkanols inhibit voltage-gated <tex>$K^{+}$</tex> channels via a distinct gating modifying mechanism that prevents gate opening
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
London :Nature Publishing Group ,
Subject
Biology
Human medicine
Engineering sciences. Technology
Source (journal)
Scientific reports. - London, 2011, currens
Volume/pages
5(2015) , 14 p.
ISSN
2045-2322
2045-2322
Article Reference
17402
Carrier
E-only publicatie
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
Full text (open access)
https://repository.uantwerpen.be/docman/irua/3a2c2b/129224.pdf
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