Ethanol Modulates BKCa Channels by Acting as an Adjuvant of Calcium
- 1 September 2008
- journal article
- Published by Elsevier in Molecular Pharmacology
- Vol. 74 (3) , 628-640
- https://doi.org/10.1124/mol.108.048694
Abstract
Ethanol modulation of calcium- and voltage-gated potassium (slo1) channels alters neuronal excitability, cerebrovascular tone, brain function, and behavior, yet the mechanism of this modulation remains unknown. Using patch-clamp electrophysiology on recombinant BKCa channels cloned from mouse brain and expressed in Xenopus laevis oocytes, we demonstrate that ethanol, even at concentrations maximally effective to modulate BKCa channel function (100 mM), fails to gate the channel in absence of activating calcium. Moreover, ethanol does not modify intrinsic, voltage- or physiological magnesium-driven gating. The alcohol works as an adjuvant of calcium by selectively facilitating calcium-driven gating. This facilitation, however, renders differential ethanol effects on channel activity: potentiation at low (10 μM) calcium, this dual pattern remaining largely unmodified by coexpression of brain slo1 channels with the neuronally abundant BKCa channel β4 subunit. Calcium recognition by either of the slo1 high-affinity sensors (calcium bowl and RCK1 Asp362/Asp367) is required for ethanol to amplify channel activation by calcium. The Asp362/Asp367 site, however, is necessary and sufficient to sustain ethanol inhibition. This inhibition also results from ethanol facilitation of calcium action; in this case, ethanol favors channel dwelling in a calcium-driven, low-activity mode. The agonist-adjuvant mechanism that we advance from the calcium-ethanol interaction on slo1 might be applicable to data of ethanol action on a wide variety of ligand-gated channels.This publication has 59 references indexed in Scilit:
- The second transmembrane domain of the large conductance, voltage‐ and calcium‐gated potassium channelβ1subunit is a lithocholate sensorFEBS Letters, 2008
- Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosisApoptosis, 2007
- Ionic Requirements for Membrane-Glass Adhesion and Giga Seal Formation in Patch-Clamp RecordingBiophysical Journal, 2007
- High-conductance potassium channels of the SLO familyNature Reviews Neuroscience, 2006
- Divalent Cation Sensitivity of BK Channel Activation Supports the Existence of Three Distinct Binding SitesThe Journal of general physiology, 2005
- Mapping the BKCa Channel's “Ca2+ Bowl”The Journal of general physiology, 2004
- Multiple regulatory sites in large-conductance calcium-activated potassium channelsNature, 2002
- Mechanism of magnesium activation of calcium-activated potassium channelsNature, 2002
- Cloning and Functional Characterization of Novel Large Conductance Calcium-activated Potassium Channel β Subunits, hKCNMB3 and hKCNMB4Journal of Biological Chemistry, 2000
- Calmodulin structure refined at 1.7 Å resolutionJournal of Molecular Biology, 1992