Molecular interaction between general anesthetics and GABAA receptor

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During the two years period supported this grant, we revealed the following two points by using the molecular biological and electrophysiological methods.1) By using the chimeric receptor studies between alpha1 and beta3 subunit of GABAA receptor, The site of action of propofol potentiation in GABAA receptor function may be in the long hydrophilic NH2 terminal of alpha1 subunit. The further mutational study of amino residues in alpha1 subunit may be necessary to elucidate the precise site for propofol site.2) The point mutation of tyrosine to phenylalanine at position 157 in beta2 subunit of GABA receptor drastically decreased the sensitivity to GABA but not anesthetics such as propofol, etomidate and pentobarbital. Also this tyrosine mutation of beta2 subunit had no influence on the modulatory actions of these anesthetics. The result suggested the distinct site of action on the direct action of GABA receptor by GABA and anesthetics and the modulatory action of anesthetics may be not mediated by GABA site.