Journal article
Methionine 286 in transmembrane domain 3 of the GABAA receptor β subunit controls a binding cavity for propofol and other alkylphenol general anesthetics
Neuropharmacology, Vol.41(8), pp.952-964
12/2001
DOI: 10.1016/S0028-3908(01)00141-1
PMID: 11747900
Abstract
γ-Aminobutyric acid type A (GABAA) receptors are an important target for general anesthetics in the central nervous system. Site-directed mutagenesis techniques have identified amino acid residues that are important for the positive modulation of GABAA receptors by general anesthetics. In the present study, we investigate the role of an amino acid residue in transmembrane (TM) domain 3 of the GABAA receptor β2 subunit for modulation by the general anesthetic 2,6-diisopropylphenol (propofol). Mutation of methionine 286 to tryptophan (M286W) in the β2 subunit abolished potentiation of GABA responses by propofol but did not affect direct receptor activation by propofol in the absence of GABA. In contrast, substitution of methionine 286 by alanine, cysteine, glutamate, lysine, phenylalanine, serine, or tyrosine was permissive for potentiation of GABA responses and direct activation by propofol. Using propofol analogs of varying molecular size, we show that the β2(M286W) mutation resulted in a decrease in the ‘cut-off’ volume for propofol analog molecules to enhance GABA responses at GABAA α1β2γ2s receptors. This suggests that mutation of M286 in the GABAA β2 subunit alters the dimensions of a ‘binding pocket’ for propofol and related alkylphenol general anesthetics.
Details
- Title: Subtitle
- Methionine 286 in transmembrane domain 3 of the GABAA receptor β subunit controls a binding cavity for propofol and other alkylphenol general anesthetics
- Creators
- M. D Krasowski - Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, USAK Nishikawa - Department of Anesthesiology, A-1050, Weill Medical College of Cornell University, 525 East 68N Nikolaeva - Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, USAA Lin - Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, USAN.L Harrison - Department of Anesthesiology, A-1050, Weill Medical College of Cornell University, 525 East 68
- Resource Type
- Journal article
- Publication Details
- Neuropharmacology, Vol.41(8), pp.952-964
- DOI
- 10.1016/S0028-3908(01)00141-1
- PMID
- 11747900
- ISSN
- 0028-3908
- eISSN
- 1873-7064
- Language
- English
- Date published
- 12/2001
- Academic Unit
- Pathology
- Record Identifier
- 9984047648202771
Metrics
16 Record Views