Abstract
Ethanol enhances the gating of a family of related ligand-gated ion channels including nicotinic acetylcholine, serotonin type 3, γ-aminobutyric acid-A, and glycine receptors. This common action may reflect shared molecular and kinetic mechanisms. In all of these receptors, ethanol enhances multichannel currents elicited with low agonist concentrations, but not with high agonist concentrations. A single mutation in the nicotinic receptor β subunit, βT263I, causes ethanol to enhance multichannel currents elicited with both low and high acetylcholine concentrations. Based on the ratios of acetylcholine EC50s in the presence and absence of ethanol, this mutant’s sensitivity to enhancement is similar to wild type. Ethanol enhancement of βT263I receptor activation shows no voltage dependence. In the presence of ethanol, the apparent single-channel conductance of the βT263I receptor is reduced and the apparent channel lifetime is lengthened. Both the 28% increase in maximal current and the 2-fold reduction in EC50 observed at 300 mM ethanol are quantitatively predicted by simulation of a simple kinetic scheme in which ethanol increases by 4-fold the ratio of microscopic opening rate (β) to closing rate (α) for acetylcholine-bound βT263I receptors. We conclude that ethanol enhancement of βT263I currents reflects stabilization of its open-channel state relative to agonist-bound closed states. Ethanol effects in wild-type receptors can also be explained by this mechanism.
Footnotes
- Received June 20, 1998.
- Accepted October 19, 1998.
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Send reprint requests to: Stuart A. Forman, Department of Anesthesia and Critical Care, CLN-3, Mass. General Hospital, Boston, MA, 02114. E-mail: forman{at}helix.mgh.harvard.edu
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This research was supported by the Massachusetts General Hospital Department of Anesthesia and Critical Care and a grant from National Institutes of Health (1-K21-AA00206, to S.A.F.). Some of these results were reported at the 1998 Research Society of Alcoholism meeting: Alcoholism (1998) 22:46A (no. 258).
- The American Society for Pharmacology and Experimental Therapeutics
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