Ethanol modulates BKCa channels by acting as an adjuvant of calcium?

Jianxi Liu, Thirumalini Vaithianathan, Kandiah Manivannan, Abby Parrill, Alejandro Dopico

Research output: Contribution to journalArticle

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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) and inhibition at high (>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.

Original languageEnglish (US)
Pages (from-to)628-640
Number of pages13
JournalMolecular Pharmacology
Volume74
Issue number3
DOIs
StatePublished - Sep 1 2008

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Ethanol
Calcium
Brain
Ligand-Gated Ion Channels
Voltage-Gated Potassium Channels
Electrophysiology
Xenopus laevis
Calcium Channels
Magnesium
Oocytes
Alcohols

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Ethanol modulates BKCa channels by acting as an adjuvant of calcium? / Liu, Jianxi; Vaithianathan, Thirumalini; Manivannan, Kandiah; Parrill, Abby; Dopico, Alejandro.

In: Molecular Pharmacology, Vol. 74, No. 3, 01.09.2008, p. 628-640.

Research output: Contribution to journalArticle

Liu, Jianxi ; Vaithianathan, Thirumalini ; Manivannan, Kandiah ; Parrill, Abby ; Dopico, Alejandro. / Ethanol modulates BKCa channels by acting as an adjuvant of calcium?. In: Molecular Pharmacology. 2008 ; Vol. 74, No. 3. pp. 628-640.
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