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Vol. 284, Issue 1, 258-268, 1998
Department of Pharmacology and Molecular Toxicology and Program in
Neuroscience, University of Massachusetts Medical School, Worcester,
Massachusetts
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, 
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
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.
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