Beta subunit M2-M3 loop conformational changes are uncoupled from alpha1 beta glycine receptor channel gating: Implications for human hereditary hyperekplexia

Shan, Qiang, Han, Lu and Lynch, Joseph W. (2011) Beta subunit M2-M3 loop conformational changes are uncoupled from alpha1 beta glycine receptor channel gating: Implications for human hereditary hyperekplexia. PLoS One, 6 11: e28105.1-e28105.11.


Author Shan, Qiang
Han, Lu
Lynch, Joseph W.
Title Beta subunit M2-M3 loop conformational changes are uncoupled from alpha1 beta glycine receptor channel gating: Implications for human hereditary hyperekplexia
Formatted title β subunit M2-M3 loop conformational changes are uncoupled from α1 β glycine receptor channel gating: Implications for human hereditary hyperekplexia
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2011-11-22
Sub-type Article (original research)
DOI 10.1371/journal.pone.0028105
Volume 6
Issue 11
Start page e28105.1
End page e28105.11
Total pages 11
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2012
Language eng
Formatted 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 α1 β 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 α1 to the exclusion of β subunit. The majority of these mutations are identified in the M2–M3 loop of the α1 subunit. Here we demonstrate that α1 β GlyR channel function is less sensitive to hyperekplexia-mimicking mutations introduced into the M2–M3 loop of the β than into the α1 subunit. This suggests that the M2–M3 loop of the a subunit dominates the β subunit in gating the α1 β 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 β subunit M2–M3 loop were uncoupled from α1 β 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 α1 β GlyR channel gating. Finally, based on analysis of α1 β chimeric receptors, we demonstrate that the structural components responsible for this are distributed throughout the β subunit, implying that the β 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 α1 β GlyR channel function are almost exclusively located in the α1 to the exclusion of the β subunit.  
Keyword Gated ion channel
Nicotinic acetylcholine receptor
Ligand binding domain
X-Ray structure
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2012 Collection
School of Biomedical Sciences Publications
 
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