Alcohol modulation of drug binding to the channel sites of the nicotinic acetylcholine receptor
Ei-Fakahany, E.F.; Miller, E.R.; Abbassy, M.A.; Eldefrawi, A.T.; Eldefrawi, M.E.
Journal of Pharmacology and Experimental Therapeutics 224(2): 289-296
1983
ISSN/ISBN: 0022-3565 PMID: 6296354 Document Number: 219576
The interactions of aliphatic alcohols (C2-C10) and 1-naphthol with the nicotinic acetylcholine receptor channel in Torpedo electric organ membranes were studied and alcohols had 2 effects. At low concentrations, they increased the initial rate of binding of [3H]perhydrohistrionicotoxin, [3H]phencyclidine and [3H]imipramine to the channel sites of the receptor in a concentration-dependent manner and at high concentrations this potentiation was reduced; they also inhibited the carbamylcholine (carb)-mediated increase in the rate of binding of the 3 3H-labeled ligands studied. There was excellent correlation of the potencies of the alcohols in these 2 effects with their membrane/buffer partition coefficients. Acetylation of 1-naphthol, which increases its hydrophobicity, reduced dramatically its effect on channel drug binding. The inhibition of carb-stimulated channel drug binding by alcohols was dependent upon carb concentration to the extent that ethanol inhibited the effect only at high carb concentrations, while it potentiated it at low carb concentrations. Pretreatment of the membranes with Naja .alpha.-toxin did not alter the alcohol effects and ethanol did not inhibit [3H]acetylcholine binding to the receptor sites, suggesting that alcohols were not binding to these receptor sites. At low concentrations, alcohols evidently potentiate channel drug binding and increase the affinity of carb for the receptor sites by binding to a 3rd kind of site, an alcohol site on the receptor/channel molecule which may be at the domains of the proteins embedded in the lipid bilayer.