Glasgow Meeting - May 2003

The GABAA receptor: An important target for intravenous general anaesthetics.

Lambert, J.J., Belelli, D., Peters, J.A., Weir, C.J. and Wildsmith, J.A.W.

The molecular mechanism whereby intravenous anaesthetics produce their dramatic behavioural effects is not known. Recently, the GABAA receptor has emerged as a putative target for mediating some of the behavioural actions of these agents. GABA acting through GABAA receptors, is the major inhibitory neurotransmitter in the mammalian central nervous system. A number of structurally diverse intravenous anaesthetics are now established, at clinically relevant concentrations, to enhance the actions of GABA acting at this receptor. The GABAA receptor is composed of five subunits drawn from a repertoire of a_1-6, b_1-3, g_1-3, d, e, q,  p and r_1-3. This subunit diversity permits the expression of ~ 30 isoforms of the GABAA receptor, which are heterogeneously expressed in the mammalian central nervous system and exhibit distinct physiological and pharmacological properties. We have recently demonstrated that the GABA-enhancing effects of etomidate are dependent upon GABAA subunit composition, with this anaesthetic exhibiting a clear selectivity for receptors containing b₂ or b₃ subunits cf. those incorporating b₁ subunits. Furthermore, this selectivity is dictated by the nature of a single amino acid located in the second transmembrane domain (TM2) of the subunit (an asparagine residue for b₂ and b₃ subunits and a serine residue for the b₁ subunit). The results of recent experiments in which etomidate has been given to mice that carry a b subunit mutation of this crucial amino acid will be described and their significance for understanding the molecular mechanism of general anaesthetics discussed.