Header

UZH-Logo

Maintenance Infos

The alpha5(H105R) mutation impairs alpha5 selective binding properties by altered positioning of the alpha5 subunit in GABAA receptors containing two distinct types of alpha subunits


Balic, E; Rudolph, U; Fritschy, J M; Mohler, H; Benke, D (2009). The alpha5(H105R) mutation impairs alpha5 selective binding properties by altered positioning of the alpha5 subunit in GABAA receptors containing two distinct types of alpha subunits. Journal of Neurochemistry, 110(1):244-254.

Abstract

GABA(A) receptors are pentameric ligand-gated ion channels that are major mediators of fast inhibitory neurotransmission. Clinically relevant GABA(A) receptor subtypes are assembled from alpha5(1-3, 5), beta1-3 and the gamma2 subunit. They exhibit a stoichiometry of two alpha, two beta and one gamma subunit, with two GABA binding sites located at the alpha/beta and one benzodiazepine binding site located at the alpha/gamma subunit interface. Introduction of the H105R point mutation into the alpha5 subunit, to render alpha5 subunit-containing receptors insensitive to the clinically important benzodiazepine site agonist diazepam, unexpectedly resulted in a reduced level of alpha5 subunit protein in alpha5(H105R) mice. In this study, we show that the alpha5(H105R) mutation did not affect cell surface expression and targeting of the receptors or their assembly into macromolecular receptor complexes but resulted in a severe reduction of alpha5-selective ligand binding. Immunoprecipitation studies suggest that the diminished alpha5-selective binding is presumably due to a repositioning of the alpha5(H105R) subunit in GABA(A) receptor complexes containing two different alpha subunits. These findings imply an important role of histidine 105 in determining the position of the alpha5 subunit within the receptor complex by determining the affinity for assembly with the gamma2 subunit.

Abstract

GABA(A) receptors are pentameric ligand-gated ion channels that are major mediators of fast inhibitory neurotransmission. Clinically relevant GABA(A) receptor subtypes are assembled from alpha5(1-3, 5), beta1-3 and the gamma2 subunit. They exhibit a stoichiometry of two alpha, two beta and one gamma subunit, with two GABA binding sites located at the alpha/beta and one benzodiazepine binding site located at the alpha/gamma subunit interface. Introduction of the H105R point mutation into the alpha5 subunit, to render alpha5 subunit-containing receptors insensitive to the clinically important benzodiazepine site agonist diazepam, unexpectedly resulted in a reduced level of alpha5 subunit protein in alpha5(H105R) mice. In this study, we show that the alpha5(H105R) mutation did not affect cell surface expression and targeting of the receptors or their assembly into macromolecular receptor complexes but resulted in a severe reduction of alpha5-selective ligand binding. Immunoprecipitation studies suggest that the diminished alpha5-selective binding is presumably due to a repositioning of the alpha5(H105R) subunit in GABA(A) receptor complexes containing two different alpha subunits. These findings imply an important role of histidine 105 in determining the position of the alpha5 subunit within the receptor complex by determining the affinity for assembly with the gamma2 subunit.

Statistics

Citations

4 citations in Web of Science®
5 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

3 downloads since deposited on 05 Oct 2009
0 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:July 2009
Deposited On:05 Oct 2009 09:28
Last Modified:05 Apr 2016 13:22
Publisher:Wiley-Blackwell
ISSN:0022-3042
Additional Information:The definitive version is available at www.blackwell-synergy.com
Publisher DOI:https://doi.org/10.1111/j.1471-4159.2009.06119.x
PubMed ID:19457072

Download

Preview Icon on Download
Filetype: PDF - Registered users only
Size: 1MB
View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations