Molecular basis for zinc potentiation at strychnine-sensitive glycine receptors

Abstract

The divalent cation Zn2+ is a potent potentiator at the strychnine-sensitive glycine receptor (GlyR). This occurs at nanomolar concentrations, which are the predicted endogenous levels of extracellular neuronal Zn2+. Using structural modeling and functional mutagenesis, we have identified the molecular basis for the elusive Zn2+ potentiation site on GlyRs and account for the differential sensitivity of GlyR α1 and GlyR α2 to Zn2+ potentiation. In addition, juxtaposed to this Zn2+ site, which is located externally on the N-terminal domain of the α subunit, another residue was identified in the nearby Cys loop, a region that is critical for receptor gating in all Cys loop ligand-gated ion channels. This residue acted as a key control element in the allosteric transduction pathway for Zn2+ potentiation, enabling either potentiation or overt inhibition of receptor activation depending upon the moiety resident at this location. Overall, we propose that Zn2+ binds to a site on the extracellular outer face of the GlyR α subunit and exerts its positive allosteric effect via an interaction with the Cys loop to increase the efficacy of glycine receptor gating. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.