TY - JOUR T1 - The GLRA1 Missense Mutation W170S Associates Lack of Zn<sup>2+</sup> Potentiation with Human Hyperekplexia JF - The Journal of Neuroscience JO - J. Neurosci. SP - 17675 LP - 17681 DO - 10.1523/JNEUROSCI.3240-13.2013 VL - 33 IS - 45 AU - Ning Zhou AU - Chen-Hung Wang AU - Shu Zhang AU - Dong Chuan Wu Y1 - 2013/11/06 UR - http://www.jneurosci.org/content/33/45/17675.abstract N2 - Hyperekplexia is a neurological disorder associated primarily with mutations in the α1 subunit of glycine receptors (GlyRs) that lead to dysfunction of glycinergic inhibitory transmission. To date, most of the identified mutations result in disruption of surface expression or altered channel properties of α1-containing GlyRs. Little evidence has emerged to support an involvement of allosteric GlyR modulation in human hyperekplexia. Here, we report that recombinant human GlyRs containing α1 or α1β subunits with a missense mutation in the α1 subunit (W170S), previously identified from familial hyperekplexia, caused remarkably reduced potentiation and enhanced inhibition by Zn2+. Interestingly, mutant α1W170Sβ GlyRs displayed no significant changes in potency or maximum response to glycine, taurine, or β-alanine. By temporally separating the potentiating and the inhibitory effects of Zn2+, we found that the enhancement of Zn2+ inhibition resulted from a loss of Zn2+-mediated potentiation. The W170S mutation on the background of H107N, which was previously reported to selectively disrupt Zn2+ inhibition, showed remarkable attenuation of Zn2+-mediated potentiation and thus indicated that W170 is an important residue for the Zn2+-mediated GlyR potentiation. Moreover, overexpressing the α1W170S subunit in cultured rat neurons confirmed the results from heterologous expression. Together, our results reveal a new zinc potentiation site on α1 GlyRs and a strong link between Zn2+ modulation and human disease. ER -