β Subunit M2-M3 loop conformational changes are uncoupled from α1 β glycine receptor channel gating: implications for human hereditary hyperekplexia.

摘要: Hereditary hyperekplexia, or startle disease, is a neuromotor disorder caused mainly by mutations that either prevent the surface expression of, modify function human heteromeric α1 β glycine receptor (GlyR) chloride channel. There as yet no explanation to why hyperekplexia channel are almost exclusively located in exclusion of subunit. The majority these identified M2–M3 loop Here we demonstrate GlyR less sensitive hyperekplexia-mimicking introduced into than This suggests α subunit dominates gating A further attempt determine possible mechanism underlying this phenomenon using voltage-clamp fluorometry technique revealed agonist-induced conformational changes were uncoupled from gating. contrast subunit, where shown be directly coupled Finally, based on analysis chimeric receptors, structural components responsible for distributed throughout implying has evolved without functional constraint normal pathway within it. Our study provides hereditary hyperekplexia-causing