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Ethanol Modulates BK_Ca Channels by Acting as an Adjuvant of Calcium

Department of Pharmacology, the University of Tennessee Health Science Center, Memphis, Tennessee (J.L., T.V., A.M.D.); Department of Chemistry, University of Memphis, Memphis, Tennessee (A.P.); Department of Physics, Astronomy, and Materials Science, Missouri State University, Springfield, Missouri (K.M.)

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 BK_Ca channels cloned from mouse brain and expressed in Xenopus laevis oocytes, we demonstrate that ethanol, even at concentrations maximally effective to modulate BK_Ca 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) and inhibition at high (>10 µM) calcium, this dual pattern remaining largely unmodified by coexpression of brain slo1 channels with the neuronally abundant BK_Ca 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.

Address correspondence to: Alex Dopico, Department of Pharmacology, the University of Tennessee Health Science Center, 874 Union Ave., Memphis, TN 38163. E-mail: adopico{at}utmem.edu

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