Journal
PLOS ONE
Volume 6, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0028105
Keywords
-
Categories
Funding
- National Health and Medical Research Council of Australia
Ask authors/readers for more resources
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 alpha 1 beta 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 alpha 1 to the exclusion of b subunit. The majority of these mutations are identified in the M2-M3 loop of the alpha 1 subunit. Here we demonstrate that alpha 1 beta GlyR channel function is less sensitive to hyperekplexia-mimicking mutations introduced into the M2-M3 loop of the b than into the alpha 1 subunit. This suggests that the M2-M3 loop of the a subunit dominates the b subunit in gating the alpha 1 beta 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 b subunit M2-M3 loop were uncoupled from alpha 1 beta GlyR channel gating. This is in contrast to the a subunit, where the M2-M3 loop conformational changes were shown to be directly coupled to alpha 1 beta GlyR channel gating. Finally, based on analysis of alpha 1 beta chimeric receptors, we demonstrate that the structural components responsible for this are distributed throughout the b subunit, implying that the b 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 alpha 1 beta GlyR channel function are almost exclusively located in the alpha 1 to the exclusion of the b subunit.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available