The interaction of general anaesthetics and neurosteroids with GABAA and glycine receptors

The positive allosteric effects of four structurally distinct general anaesthetics (propofol, pentobarbitone, etomidate and 5 alpha-pregnan-3 alpha-ol-20-one [5 alpha 3 alpha]) upon recombinant GABA(A) (alpha(6)beta(3)gamma(2L)), invertebrate GABA (RDL) and glycine (alpha(1)) receptors expressed in Xenopus laevis oocytes have been determined. Propofol and pentobarbitone enhanced agonist (GABA or glycine as appropriate)-evoked currents at GABA(A), glycine, and RDL receptors, whereas etomidate and 5 alpha 3 alpha were highly selective for the GABAA receptor. Utilizing site-directed mutagenesis, we demonstrate that the nature of the interaction of propofol, pentobarbitone and etomidate (but not 5 alpha 3 alpha) with mammalian and invertebrate ionotropic GABA receptors depends critically upon the nature of a single amino acid located in the second transmembrane region (TM2) of these receptors. These data are discussed in relation to the specificity of action of general anaesthetics. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.