SITES OF ALCOHOL AND VOLATILE ANESTHETIC ACTION ON GABA(A) AND GLYCINE RECEPTORS

Volatile anaesthetics have historically been considered to act in a no nspecific manner on the central nervous system(1,2). More recent studi es, however, have revealed that the receptors for inhibitory neurotran smitters such as gamma-aminobutyric acid (GABA) and glycine are sensit ive to clinically relevant concentrations of inhaled anaesthetics(3). The function of GABAA and glycine receptors is enhanced by a number of anaesthetics(4-9) and alcohols(10-12), whereas activity of the relate d(13) GABA rho 1 receptor is reduced(14). We have used this difference in pharmacology to investigate the molecular basis for modulation of these receptors by anaesthetics and alcohols. By using chimaeric recep tor constructs, we have identified a region of 45 amino-acid residues that is both necessary and sufficient for the enhancement of receptor function. Within this region, two specific amino-acid residues in tran smembrane domains 2 and 3 are critical for allosteric modulation of bo th GABA(A) and glycine receptors by alcohols and two volatile anaesthe tics. These observations support the idea that anaesthetics exert a sp ecific effect on these ion-channel proteins, and allow fbr the future testing of specific hypotheses of the action of anaesthetics.