A single amino acid confers barbiturate sensitivity upon the GABA rho 1 receptor.
Many structurally diverse general anaesthetics enhance inhibitory neurotransmission in the central nervous system by interacting with the GABAA receptor. By contrast, GABA receptors composed of the rho 1 subunit are anaesthetic-insensitive. Here, we demonstrate that both delta-hexachlorocyclohexane (delta-HCH; 1-100 microM), a positive allosteric modulator of the GABAA receptor, and the anaesthetic pentobarbitone (10-600 microM) have no effect on GABA-evoked currents mediated by wild-type rho 1 recombinant receptors (expressed in Xenopus laevis oocytes). By contrast, these agents produce up to a 10 fold enhancement of GABA responses transduced by a rho 1 receptor in which a transmembrane located isoleucine residue is replaced by serine. However, not all general anaesthetics were similarly influenced by this mutation, because propofol and 5 beta-pregnan-3 alpha-ol-20-one (5 beta 3 alpha) remained ineffective. These data are discussed in relation to the specificity of general anaesthetic action.
Department of Pharmacology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Scotland. d.belelli@dundee.ac.uk
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D018681:Anesthetics, General / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D001556:Hexachlorocyclohexane / Q000494:pharmacology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007532:Isoleucine / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009865:Oocytes / Q000502:physiology; D010424:Pentobarbital / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012694:Serine / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology
D018681:Anesthetics, General; D002492:Central Nervous System Depressants; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D007532:Isoleucine; C086916:delta-hexachlorocyclohexane; D012694:Serine; D005680:gamma-Aminobutyric Acid; D001556:Hexachlorocyclohexane; D010424:Pentobarbital