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