Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors

Abstract

Volatile anaesthetics have historically been considered to act in a nonspecific manner on the central nervous system^1,2. More recent studies, however, have revealed that the receptors for inhibitory neurotransmitters such as γ-aminobutyric acid (GABA) and glycine are sensitive to clinically relevant concentrations of inhaled anaesthetics³. The function of GABA_A and glycine receptors is enhanced by a number of anaesthetics^4,5,6,7,8,9 and alcohols^10,11,12, whereas activity of the related¹³ GABA ρ1 receptor is reduced¹⁴. We have used this difference in pharmacology to investigate the molecular basis for modulation of these receptors by anaesthetics and alcohols. By using chimaeric receptor 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 transmembrane domains 2 and 3 are critical for allosteric modulation of both GABA_A and glycine receptors by alcohols and two volatile anaesthetics. These observations support the idea that anaesthetics exert a specific effect on these ion-channel proteins, and allow for the future testing of specific hypotheses of the action of anaesthetics.