The Interaction of the General Anesthetic Etomidate with the γ -Aminobutyric Acid Type a Receptor is Influenced by a Single Amino Acid

The γ -aminobutyric acid type A (GABAA) receptor is a transmitter-gated ion channel mediating the majority of fast inhibitory synaptic transmission within the brain. The receptor is a pentameric assembly of subunits drawn from multiple classes (α1-6, β1-3, γ1-3, δ1, and ε1). Positive allosteric modu...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-09, Vol.94 (20), p.11031-11036
Main Authors: Belelli, Delia, Lambert, Jeremy J., Peters, John A., Wafford, Keith, Whiting, Paul J.
Format: Article
Language:English
Subjects:
Acids
Agonists
Amino acids
Amino Acids - chemistry
Amino Acids - metabolism
Anesthesia
Anesthetics
Anesthetics, Intravenous - metabolism
Animals
Biological Sciences
Cells, Cultured
Cerebellum - cytology
Cerebellum - metabolism
Chimeras
Cloning, Molecular
Cytoplasmic Granules - metabolism
DNA, Complementary
Drug interactions
Etomidate - metabolism
General anesthetics
Humans
Ion channels
Mice
Mutagenesis, Site-Directed
Neurons - cytology
Neurons - metabolism
Oocytes
Patch-Clamp Techniques
Pharmacology
Protein isoforms
Proteins
Rats
Rats, Wistar
Receptors
Receptors, GABA-A - chemistry
Receptors, GABA-A - genetics
Receptors, GABA-A - metabolism
Xenopus laevis
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Summary:The γ -aminobutyric acid type A (GABAA) receptor is a transmitter-gated ion channel mediating the majority of fast inhibitory synaptic transmission within the brain. The receptor is a pentameric assembly of subunits drawn from multiple classes (α1-6, β1-3, γ1-3, δ1, and ε1). Positive allosteric modulation of GABAAreceptor activity by general anesthetics represents one logical mechanism for central nervous system depression. The ability of the intravenous general anesthetic etomidate to modulate and activate GABAAreceptors is uniquely dependent upon the β subunit subtype present within the receptor. Receptors containing β2- or β3-, but not β1subunits, are highly sensitive to the agent. Here, chimeric β1/β2subunits coexpressed in Xenopus laevis oocytes with human α6and γ2subunits identified a region distal to the extracellular N-terminal domain as a determinant of the selectivity of etomidate. The mutation of an amino acid (Asn-289) present within the channel domain of the β3subunit to Ser (the homologous residue in β1), strongly suppressed the GABA-modulatory and GABA-mimetic effects of etomidate. The replacement of the β1subunit Ser-290 by Asn produced the converse effect. When applied intracellularly to mouse L(tk-) cells stably expressing the α6β3γ2subunit combination, etomidate was inert. Hence, the effects of a clinically utilized general anesthetic upon a physiologically relevant target protein are dramatically influenced by a single amino acid. Together with the lack of effect of intracellular etomidate, the data argue against a unitary, lipid-based theory of anesthesia.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.20.11031