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Journal of Neuroscience, Vol 14, 5453-5460, Copyright © 1994 by Society for Neuroscience
Ethanol directly modulates gating of a dihydropyridine-sensitive Ca2+ channel in neurohypophysial terminals
X Wang, G Wang, JR Lemos and SN Treistman
Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655.
Ingestion of ethanol results in a decreased level of plasma vasopressin,
which appears to be caused by inhibition of arginine vasopressin (AVP)
release from the neurohypophysis. Activation of membrane voltage-gated Ca2+
channels plays an important role in triggering this neurohormone release.
In this article, single-channel recordings are used to demonstrate that
ethanol, at concentrations constituting legal intoxication, inhibits
dihydropyridine-sensitive "L- type" Ca2+ channels in isolated nerve
terminals of the rat neurohypophysis. Ethanol reduced the channel open
probability in a concentration-dependent manner. To allow finer resolution
of channel openings and to better characterize the mechanisms of ethanol
action, Bay K 8644 was used to prolong the openings of L-type Ca2+
channels. In the presence of this dihydropyridine (DHP), the reduction of
the channel open probability by concentrations of ethanol of 25 mM or
higher could be determined to be due primarily, although not completely, to
a shortening of the open duration of this L-channel. Channel conductance
was unaffected by ethanol, even at high concentrations. These results are
consistent with previous macroscopic data indicating that calcium channels
in these peptidergic terminals are targets for ethanol action, and indicate
that ethanol acts directly on the gating characteristics of the L-type
channel. Furthermore, examination of open and closed state transitions, as
well as Hill plot analysis, suggests that ethanol's effects on gating are
consistent with the interaction of a single drug molecule with a single
target site, possibly the L-channel itself.
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