The inhibitory tone maintained throughout the central nervous system relies predominantly on the activity of neuronal GABAA (γ-aminobutyric acid type A) receptors. This receptor family comprises various subtypes that have unique regional distributions, but little is known about the role played by each subtype. The majority of the receptors contain a γ2 subunit and are sensitive to modulation by BZs (benzodiazepines), but differ with regard to α and β subunits. Mutagenesis studies combined with molecular modelling have enabled a greater understanding of receptor structure and dynamics. This can now be extended to in vivo activity through translation to genetically modified mice containing these mutations. Ideally, the mutation should leave normal receptor function intact, and this is the case with mutations affecting the BZ-binding site of the GABAA receptor. We have generated mutations, which affect the BZ site of different α subunits, to enable discrimination of the various behavioural consequences of BZ drug action. This has aided our understanding of the roles played by individual GABAA receptor subtypes in particular behaviours. We have also used this technique to explore the role of different β subunits in conferring the anaesthetic activity of etomidate. This technique together with the development of subtype-selective compounds facilitates our understanding of the roles played by each receptor subtype.
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Conference Article|
June 01 2004
Differentiating the role of γ-aminobutyric acid type A (GABAA) receptor subtypes
K.A. Wafford;
K.A. Wafford
1
Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
1To whom correspondence should be addressed (email keith_wafford@merck.com).
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A.J. Macaulay;
A.J. Macaulay
Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
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R. Fradley;
R. Fradley
Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
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G.F. O'Meara;
G.F. O'Meara
Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
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D.S. Reynolds;
D.S. Reynolds
Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
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T.W. Rosahl
T.W. Rosahl
Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
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Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2004 Biochemical Society
2004
Biochem Soc Trans (2004) 32 (3): 553–556.
Citation
K.A. Wafford, A.J. Macaulay, R. Fradley, G.F. O'Meara, D.S. Reynolds, T.W. Rosahl; Differentiating the role of γ-aminobutyric acid type A (GABAA) receptor subtypes. Biochem Soc Trans 1 June 2004; 32 (3): 553–556. doi: https://doi.org/10.1042/bst0320553
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