The interaction of general anaesthetics and neurosteroids with GABA(A) and glycine receptors.
The positive allosteric effects of four structurally distinct general anaesthetics (propofol, pentobarbitone, etomidate and 5alpha-pregnan-3alpha-ol-20-one [5alpha3alpha]) upon recombinant GABA(A) (alpha6beta3gamma2L), invertebrate GABA (RDL) and glycine (alpha1) 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 5alpha3alpha were highly selective for the GABA(A) receptor. Utilizing site-directed mutagenesis, we demonstrate that the nature of the interaction of propofol, pentobarbitone and etomidate (but not 5alpha3alpha) 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.
Neurosciences Institute, Department of Pharmacology & Neuroscience, Ninewells Hospital & Medical School, Dundee University, UK.
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D
Belelli
M
M
Pistis
J A
JA
Peters
J J
JJ
Lambert
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D004347:Drug Interactions; D004553:Electric Conductivity; D005045:Etomidate / Q000494:pharmacology; D005260:Female; D005998:Glycine / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D018009:Receptors, Glycine / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000777:Anesthetics; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone; D010424:Pentobarbital; D005998:Glycine; D015742:Propofol; D005045:Etomidate