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- Title
Zinc-mediated inhibition of GABA<sub>A</sub> receptors: discrete binding sites underlie subtype specificity.
- Authors
Hosie, Alastair M.; Dunne, Emma L.; Harvey, Robert J.; Smart, Trevor G.
- Abstract
Zinc ions are concentrated in the central nervous system and regulate GABA[SUBA] receptors, which are pivotal mediators of inhibitory synaptic neurotransmission. Zinc ions inhibit GABA[SUBA] receptor function by an allosteric mechanism that is critically dependent on the receptor subunit composition: αβ subunit combinations show the highest sensitivity, and αβγ 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 Zn[SUP2+] 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 α and β subunits. We found that the characteristically low Zn[SUP2+] sensitivity of GABA[SUBA] receptors containing the γ2 subunit results from disruption to two of the three sites after receptor subunit co-assembly.
- Publication
Nature Neuroscience, 2003, Vol 6, Issue 4, p362
- ISSN
1097-6256
- Publication type
Academic Journal
- DOI
10.1038/nn1030