A histidine residue in the extracellular N-terminal domain of the GABA(A) receptor alpha5 subunit regulates sensitivity to inhibition by zinc.

The divalent cation zinc is abundant in the brain, particularly in the mossy fibers of the hippocampus. Recent evidence suggests that zinc is packaged into some synaptic vesicles in this region and can be co-released with neurotransmitter. Zinc inhibits the activity of GABA(A) receptors and the sensitivity of the receptor to zinc is influenced by its alpha subunit subtype composition. The alpha4, alpha5 and alpha6 subunits confer greater sensitivity to zinc than receptors containing other alpha subunits. The alpha4 and alpha5 subunits are highly expressed in hippocampal neurons, and likely mediate any effects of zinc on GABAergic neurotransmission in this area. The alpha5 subunit contains a unique histidine residue in the N-terminal extracellular domain while the other alpha subunits have an aspartate residue in this location. Point mutations were created to exchange the histidine and aspartate residues of the alpha1 and alpha5 subunits. Receptors containing the mutated alpha5((H195D)) subunit had reduced sensitivity to zinc, while alpha1((D191H))beta3gamma2L receptors had increased sensitivity to zinc, similar to the alpha5beta3gamma2L wild type receptors. These findings indicate that histidine195 of the alpha5 subunit plays an important role in determining the sensitivity of recombinant GABA(A) receptors to zinc.