Zinc-mediated inhibition of GABAA receptors: discrete binding sites underlie subtype specificity

A M Hosie; E L Dunne; Robert J Harvey; T G Smart

doi:10.1038/nn1030

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Zinc-mediated inhibition of GABAA receptors: discrete binding sites underlie subtype specificity

Journal article

Peer reviewed

Zinc-mediated inhibition of GABAA receptors: discrete binding sites underlie subtype specificity

A M Hosie, E L Dunne, Robert J Harvey and T G Smart

Nature Neuroscience, Vol.6(4), pp.362-369

2003

DOI: https://doi.org/10.1038/nn1030

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Abstract

Neurosciences

Cognitive Sciences

Zinc ions are concentrated in the central nervous system and regulate GABAA receptors, which are pivotal mediators of inhibitory synaptic neurotransmission. Zinc ions inhibit GABAA receptor function by an allosteric mechanism that is critically dependent on the receptor subunit composition: alphabeta subunit combinations show the highest sensitivity, and alphabetabold gamma isoforms are the least sensitive. Here we propose a mechanistic and structural basis for this inhibition and its dependence on the receptor subunit composition. We used molecular modeling to identify three discrete sites that mediate Zn2+ inhibition. One is located within the ion channel, and the other two are on the external amino (N)-terminal face of the receptor at the interfaces between alpha and beta subunits. We found that the characteristically low Zn2+ sensitivity of GABAA receptors containing the bold gamma2 subunit results from disruption to two of the three sites after receptor subunit co-assembly.

Details

Title: Zinc-mediated inhibition of GABAA receptors: discrete binding sites underlie subtype specificity
Authors: A M Hosie (Author) - University College London, United Kingdom
E L Dunne (Author) - University College London, United Kingdom
Robert J Harvey (Author) - University College London, United Kingdom
T G Smart (Author) - University College London, United Kingdom
Publication details: Nature Neuroscience, Vol.6(4), pp.362-369
Publisher: Nature Publishing Group
Date published: 2003
DOI: 10.1038/nn1030
ISSN: 1097-6256
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99451083002621
Output Type: Journal article

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