? Subunit M2-M3 loop conformational changes are uncoupled from ?1 ? glycine receptor channel gating: implications for human hereditary hyperekplexia.

ABSTRACT: Hereditary hyperekplexia, or startle disease, is a neuromotor disorder caused mainly by mutations that either prevent the surface expression of, or modify the function of, the human heteromeric ?1 ? glycine receptor (GlyR) chloride channel. There is as yet no explanation as to why hyperekplexia mutations that modify channel function are almost exclusively located in the ?1 to the exclusion of ? subunit. The majority of these mutations are identified in the M2-M3 loop of the ?1 subunit. Here we demonstrate that ?1 ? GlyR channel function is less sensitive to hyperekplexia-mimicking mutations introduced into the M2-M3 loop of the ? than into the ?1 subunit. This suggests that the M2-M3 loop of the ? subunit dominates the ? subunit in gating the ?1 ? GlyR channel. A further attempt to determine the possible mechanism underlying this phenomenon by using the voltage-clamp fluorometry technique revealed that agonist-induced conformational changes in the ? subunit M2-M3 loop were uncoupled from ?1 ? GlyR channel gating. This is in contrast to the ? subunit, where the M2-M3 loop conformational changes were shown to be directly coupled to ?1 ? GlyR channel gating. Finally, based on analysis of ?1 ? chimeric receptors, we demonstrate that the structural components responsible for this are distributed throughout the ? subunit, implying that the ? subunit has evolved without the functional constraint of a normal gating pathway within it. Our study provides a possible explanation of why hereditary hyperekplexia-causing mutations that modify ?1 ? GlyR channel function are almost exclusively located in the ?1 to the exclusion of the ? subunit.

SUBMITTER: Shan Q 

PROVIDER: S-EPMC3222680 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature