The GLRA1 Missense Mutation W170S Associates Lack of Zn2+Potentiation with Human Hyperekplexia

• DOI: 10.1523/jneurosci.3240-13.2013
• Publication Date: 2013-11-06T17:40:09Z
• Authors: Ning Zhou; Chen-Hung Wang; Shu Zhang; Dong Chuan Wu
• Keywords: Male; Neurons; 0301 basic medicine; Reflex, Abnormal; Mutation, Missense; Stiff-Person Syndrome; Rats; Zinc; 03 medical and health sciences; Receptors, Glycine; Animals; Humans; Female

Hyperekplexia is a neurological disorder associated primarily with mutations in the α1 subunit of glycine receptors (GlyRs) that lead to dysfunction glycinergic inhibitory transmission. To date, most identified result disruption surface expression or altered channel properties α1-containing GlyRs. Little evidence has emerged support an involvement allosteric GlyR modulation human hyperekplexia. Here, we report recombinant GlyRs containing α1β subunits missense mutation (W170S), previously from familial hyperekplexia, caused remarkably reduced potentiation and enhanced inhibition by Zn 2+ . Interestingly, mutant W170S β displayed no significant changes potency maximum response glycine, taurine, β-alanine. By temporally separating potentiating effects , found enhancement resulted loss -mediated potentiation. The on background H107N, which was reported selectively disrupt inhibition, showed remarkable attenuation thus indicated W170 important residue for Moreover, overexpressing cultured rat neurons confirmed results heterologous expression. Together, our reveal new zinc site strong link between disease.