Ethanol increases the activity of Ca++ -dependent K+ (mslo) channels: Functional interaction with cytosolic Ca++

Alejandro Dopico, Vellareddy Anantharam, Steven N. Treistman

Research output: Contribution to journalArticle

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Abstract

Ethanol (EtOH) reversibly activates large conductance, Ca++ -activated K+ (BK) channels in rat neurohypophysial terminals, an effect that probably contributes to the inhibition of vasopressin release by this drug. Heterogeneity in the terminal channel population makes it difficult to determine the mechanisms underlying this activation. Here, we report the effects of EtOH on the steady-state activity of BK channels cloned from mouse brain (mslo, α subunit) and expressed in Xenopus oocytes. EtOH reversibly increased mslo channel activity in excised patches, showing a potency (EC50 = 24 mM) similar to that reported using native channels. EtOH activation was observed under conditions that make it highly improbable that it is mediated by freely diffusible second messengers, or secondary to G-protein modulation. Rather, it probably results from a functional interaction between the drug and the channel α subunit. Activation occurred without increase in the number of functional channels present in the patch and resulted from actions that were a function of EtOH concentration: at ≤10 mM, activation was due to a decrease in the channel mean closed time, whereas between 25 and 100 mM, activation was due to both a decrease in the mean closed time and an increase in the mean open time. The characteristic high unitary conductance and ionic selectivity of BK channels were unaltered by the drug. Whereas the voltage dependence of channel gating remained unchanged, channel activation mediated by the response of the Ca++ -sensing site(s) to increases in the concentration of intracellular calcium, [Ca++](ic), was reduced by EtOH. This finding is consistent with EtOH and [Ca++](ic) behaving functionally as partial and full agonists of mslo channels, respectively. Because the potentiation of mslo activity by the drug decreased as Ca++ levels were increased, EtOH-activation of BK channels would be most evident when [Ca++](ic) is near resting levels, rather than during periods of high activity and Ca++ influx.

Original languageEnglish (US)
Pages (from-to)258-268
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume284
Issue number1
StatePublished - Jan 1 1998

Fingerprint

Large-Conductance Calcium-Activated Potassium Channels
Ethanol
Second Messenger Systems
Xenopus
Vasopressins
Drug Interactions
GTP-Binding Proteins
Pharmaceutical Preparations
Oocytes
Calcium
Brain
Population

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Ethanol increases the activity of Ca++ -dependent K+ (mslo) channels : Functional interaction with cytosolic Ca++. / Dopico, Alejandro; Anantharam, Vellareddy; Treistman, Steven N.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 284, No. 1, 01.01.1998, p. 258-268.

Research output: Contribution to journalArticle

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