Analysis of hyperekplexia mutations identifies transmembrane domain rearrangements that mediate glycine receptor activation

Bode, Anna and Lynch, Joseph W. (2013) Analysis of hyperekplexia mutations identifies transmembrane domain rearrangements that mediate glycine receptor activation. Journal of Biological Chemistry, 288 47: 33760-33771. doi:10.1074/jbc.M113.513804

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Author Bode, Anna
Lynch, Joseph W.
Title Analysis of hyperekplexia mutations identifies transmembrane domain rearrangements that mediate glycine receptor activation
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2013-11-22
Year available 2013
Sub-type Article (original research)
DOI 10.1074/jbc.M113.513804
Open Access Status File (Author Post-print)
Volume 288
Issue 47
Start page 33760
End page 33771
Total pages 12
Place of publication Bethesda, MD United States
Publisher American Society for Biochemistry and Molecular Biology Inc
Language eng
Subject 1303 Specialist Studies in Education
1307 Cell Biology
1312 Molecular Biology
Abstract Pentameric ligand-gated ion channels (pLGICs) mediate numerous physiological processes and are therapeutic targets for a wide range of clinical indications. Elucidating the structural differences between their closed and open states may help in designing improved drugs that bias receptors toward the desired conformational state. We recently showed that two new hyperekplexia mutations, Q226E and V280M, induced spontaneous activity in α1 glycine receptors. Gln-226, located near the top of transmembrane (TM) 1, is closely apposed to Arg-271 at the top of TM2 in the neighboring subunit. Using mutant cycle analysis, we inferred that Q226E induces activation via an enhanced electrostatic attraction to Arg-271. This would tilt the top of TM2 toward TM1 and hence away from the pore axis to open the channel. We also concluded that the increased side chain volume of V280M, in the TM2-TM3 loop, exerts a steric repulsion against Ile-225 at the top of TM1 in the neighboring subunit. We infer that this steric repulsion would tilt the top of TM3 radially outwards against the stationary TM1 and thus provide space for TM2 to relax away from the pore axis to create an open channel. Because the transmembrane domain movements inferred from this functional analysis are consistent with the structural differences evident in the x-ray atomic structures of closed and open state bacterial pLGICs, we propyose that the model of pLGIC activation as outlined here may be broadly applicable across the eukaryotic pLGIC receptor family.
Keyword Cys Loop Receptors
Glycine receptors
Patch Clamp
Receptor Structure Function
Site directed mutagenesis
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 2014 Collection
School of Biomedical Sciences Publications
 
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