A SINGLE AMINO-ACID DETERMINES DIFFERENCES IN ETHANOL ACTIONS ON STRYCHNINE-SENSITIVE GLYCINE RECEPTORS

Effects of ethanol on strychnine-sensitive glycine receptors were stud ied in Xenopus laevis oocytes expressing alpha(1) wildtype, alpha(2), or mutant alpha(1)(A52S) homomeric glycine receptors. This alpha(1)(A5 2S) mutant, in which a serine residue substitutes for alanine at amino acid 52, is responsible for the spasmodic phenotype in mice and alter s the ability of glycine to activate the receptor. Pharmacologically r elevant concentrations of ethanol (10-200 mM) reversibly potentiated t he glycine receptor function in all receptors. Ethanol potentiation de pended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. Homomeric alpha(1) glycine receptors were more sensitive to the effects of ethanol than were alph a(2) or the mutant alpha(1)(A52S) receptors. No differences were found in ethanol sensitivity between alpha(2) and the mutant alpha(1)(A52S) receptors. The alpha(2) subunit has a threonine residue, a conservati ve substitution for serine, at amino acid 52. The general anesthetic p ropofol was also tested in homomeric alpha(1), alpha(2), or the mutant alpha(1)(A52S) receptors. Propofol, at unaesthetic concentrations (1- 5 mu M), reversibly potentiated the glycine receptor function in a con centration-dependent manner and to an equal extent in the three subuni ts tested. These data suggest that the mutation of an alanine to serin e at amino acid 52 of the alpha subunit is responsible for the differe nce in ethanol sensitivity seen in homomeric receptors composed of alp ha(1) and alpha(2) subunits.