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Mutational analysis of molecular requirements for the actions of general anaesthetics at the γ-aminobutyric acidA receptor subtype, α1β2γ2


Siegwart, R C; Krähenbühl, K; Lambert, S; Rudolph, U (2003). Mutational analysis of molecular requirements for the actions of general anaesthetics at the γ-aminobutyric acidA receptor subtype, α1β2γ2. BMC Pharmacology, 3:13.

Abstract

BACKGROUND: Amino acids in the beta subunit contribute to the action of general anaesthetics on GABA(A) receptors. We have now characterized the phenotypic effect of two beta subunit mutations in the most abundant GABA(A) receptor subtype, alpha1beta2gamma2. RESULTS: The beta2(N265M) mutation in M2 decreased the modulatory actions of propofol, etomidate and enflurane, but not of alphaxalone, while the direct actions of propofol, etomidate and alphaxalone were impaired. The beta2(M286W) mutation in M3 decreased the modulatory actions of propofol, etomidate and enflurane, but not of alphaxalone, whereas the direct action of propofol and etomidate, but not of alphaxalone, was impaired. CONCLUSIONS: We found that the actions of general anaesthetics at alpha1beta2(N265M)gamma2 and alpha1beta2(M286W)gamma2 GABA(A) receptors are similar to those previously observed at alpha2beta3(N265M)gamma2 and alpha2beta3(M286W)gamma2 GABA(A) recpetors, respectively, with the notable exceptions that the direct action of propofol was decreased in alpha1beta2(M286W)gamma2 receptors but indistinguishable form wild type in alpha2beta3(M286W)gamma2 receptors and that the direct action of alphaxalone was decreased in alpha1beta2(N265M)gamma2 but not alpha2beta3(N265M)gamma2 receptors and indistinguishable form wild type in alpha1beta2(M286W)gamma2 receptors but increased in alpha2beta3(M286W)gamma2 receptors. Thus, selected phenotypic consequences of these two mutations are GABA(A) receptor subtype-specific.

BACKGROUND: Amino acids in the beta subunit contribute to the action of general anaesthetics on GABA(A) receptors. We have now characterized the phenotypic effect of two beta subunit mutations in the most abundant GABA(A) receptor subtype, alpha1beta2gamma2. RESULTS: The beta2(N265M) mutation in M2 decreased the modulatory actions of propofol, etomidate and enflurane, but not of alphaxalone, while the direct actions of propofol, etomidate and alphaxalone were impaired. The beta2(M286W) mutation in M3 decreased the modulatory actions of propofol, etomidate and enflurane, but not of alphaxalone, whereas the direct action of propofol and etomidate, but not of alphaxalone, was impaired. CONCLUSIONS: We found that the actions of general anaesthetics at alpha1beta2(N265M)gamma2 and alpha1beta2(M286W)gamma2 GABA(A) receptors are similar to those previously observed at alpha2beta3(N265M)gamma2 and alpha2beta3(M286W)gamma2 GABA(A) recpetors, respectively, with the notable exceptions that the direct action of propofol was decreased in alpha1beta2(M286W)gamma2 receptors but indistinguishable form wild type in alpha2beta3(M286W)gamma2 receptors and that the direct action of alphaxalone was decreased in alpha1beta2(N265M)gamma2 but not alpha2beta3(N265M)gamma2 receptors and indistinguishable form wild type in alpha1beta2(M286W)gamma2 receptors but increased in alpha2beta3(M286W)gamma2 receptors. Thus, selected phenotypic consequences of these two mutations are GABA(A) receptor subtype-specific.

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Additional indexing

Other titles:Mutational analysis of molecular requirements for the actions of general anaesthetics at the gamma-aminobutyric acidA receptor subtype, alpha1beta2gamma2
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2003
Deposited On:11 Feb 2008 12:19
Last Modified:05 Apr 2016 12:16
Publisher:BioMed Central
ISSN:1472-6904
Additional Information:Free full text article
Publisher DOI:10.1186/1471-2210-3-13
Official URL:http://www.biomedcentral.com/content/pdf/1471-2210-3-13.pdf
PubMed ID:14613517
Permanent URL: http://doi.org/10.5167/uzh-875

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