Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity

Zinc ions are concentrated in the central nervous system and regulate GABA(A) receptors, which are pivotal mediators of inhibitory synaptic neurotransmission. Zinc ions inhibit GABA(A) receptor function by an allosteric mechanism that is critically dependent on the receptor subunit composition: alphabeta subunit combinations show the highest sensitivity, and alphabetagamma 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 GABA(A) receptors containing the gamma2 subunit results from disruption to two of the three sites after receptor subunit co-assembly.