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1 The GABA modulating and GABA-mimetic actions of the general anaesthetic etomidate were examined in voltage-clamp recordings performed on Xenopus laevis oocytes induced, by cRNA injection, to express human recombinant g-aminobutyric acid A (GABA A ) receptor subunits. 2 Currents mediated by recombinant receptors with the ternary subunit composition a x b y g 2L (where x=1,2,3 or 6 and y=1 or 2), in response to GABA applied at the appropriate EC 10 , were enhanced by etomidate in a manner that was dependent upon the identity of both the a and b subunit isoforms. 3 For the b 2 -subunit containing receptors tested, the EC 50 for the potentiation of GABA-evoked currents by etomidate (range 0.6 to 1.2 mM) was little aected by the nature of the a subunit present within the hetero-oligomeric complex. However, replacement of the b 2 by the b 1 subunit produced a 9 ± 12 fold increase in the etomidate EC 50 (6 to 11 mM) for all a-isoforms tested. 4 For a 1 , a 2 and a 6 , but not a 3 -subunit containing receptors, the maximal potentiation of GABAevoked currents by etomidate was greater for b 2 -than for b 1 -subunit containing receptors. This was most clearly exempli®ed by receptors composed of a 6 b 1 g 2L compared to a 6 b 2 g 2L subunits, where a maximally eective concentration of etomidate potentiated currents evoked by GABA at EC 10 to 28+2% and 169+4% of the maximal GABA response, respectively. 5 For a 1 subunit-containing receptors, the potency and maximal potentiating eect of either pentobarbitone or propofol was essentially unaected by the b subunit isoform contained within the receptor complex. The potency of the anaesthetic neurosteroid 5a-pregnan-3a-ol-20-one was marginally higher for b 1 rather than the b 2 subunit-containing receptor, although its maximal eect was similar at the two receptor isoforms. 6 The GABA-mimetic action of etomidate was supported by b 2 -but not b 1 -subunit containing receptors, whereas that of pentobarbitone or propofol was evident with either b isoform. For b 2 -subunit containing receptors, both the agonist EC 50 and the maximal current produced by etomidate were additionally in¯uenced by the a isoform. 7 It is concluded that the subtype of b-subunit in¯uences the potency with which etomidate potentiates GABA-evoked currents and that the b isoform is a crucial determinant of the GABA-mimetic activity of this compound. The nature of the a-subunit also impacts upon the maximal potentiation and activation that the compound may elicit. Such pronounced in¯uences may aid the identi®cation of the site that recognises etomidate. More generally, these results provide a clear example of structural speci®city in anaesthetic action.

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