An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel

Anna Bukiya, Guruprasad Kuntamallappanavar, Justin Edwards, Aditya K. Singh, Bangalore Shivakumar, Alejandro Dopico

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Ethanol alters BK (slo1) channel function leading to perturbation of physiology and behavior. Site(s) and mechanism(s) of ethanol-BK channel interaction are unknown. We demonstrate that ethanol docks onto a water-accessible site that is strategically positioned between the slo1 calcium-sensors and gate. Ethanol only accesses this site in presence of calcium, the BK channel's physiological agonist. Within the site, ethanol hydrogen-bonds with K361. Moreover, substitutions that hamper hydrogen bond formation or prevent ethanol from accessing K361 abolish alcohol action without altering basal channel function. Alcohol interacting site dimensions are approximately 10.7 x 8.6 x 7.1 Å, accommodating effective (ethanol-heptanol) but not ineffective (octanol, nonanol) channel activators. This study presents: (i) to our knowledge, the first identification and characterization of an n-alkanol recognition site in a member of the voltage-gated TM6 channel superfamily; (ii ) structural insights on ethanol allosteric interactions with ligand-gated ion channels; and (iii) a first step for designing agents that antagonize BK channel-mediated alcohol actions without perturbing basal channel function.

Original languageEnglish (US)
Pages (from-to)9313-9318
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number25
DOIs
StatePublished - Jun 24 2014

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Large-Conductance Calcium-Activated Potassium Channels
Potassium Channels
Ethanol
Alcohols
Calcium
Hydrogen
Heptanol
Ligand-Gated Ion Channels
Octanols
Calcium Channels
Water

All Science Journal Classification (ASJC) codes

  • General

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An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel. / Bukiya, Anna; Kuntamallappanavar, Guruprasad; Edwards, Justin; Singh, Aditya K.; Shivakumar, Bangalore; Dopico, Alejandro.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 25, 24.06.2014, p. 9313-9318.

Research output: Contribution to journalArticle

Bukiya, Anna ; Kuntamallappanavar, Guruprasad ; Edwards, Justin ; Singh, Aditya K. ; Shivakumar, Bangalore ; Dopico, Alejandro. / An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 25. pp. 9313-9318.
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