A comparison of glycine-and ivermectin-mediated conformational changes in the glycine receptor ligand-binding domain

Wang, Qian and Lynch, Joseph W. (2012) A comparison of glycine-and ivermectin-mediated conformational changes in the glycine receptor ligand-binding domain. International Journal of Biochemistry and Cell Biology, 44 2: 335-340.


Author Wang, Qian
Lynch, Joseph W.
Title A comparison of glycine-and ivermectin-mediated conformational changes in the glycine receptor ligand-binding domain
Journal name International Journal of Biochemistry and Cell Biology  (ERA 2012 Listed)    (ERA 2010 Rank B)   Check publisher's open access policy
Publication date 2012-02
Sub-type Article
Year available 2011
DOI 10.1016/j.biocel.2011.11.005
Volume number 44
Issue number 2
ISSN 1357-2725
1878-5875
Start page 335
End page 340
Total pages 6
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon
Collection year 2012
Language eng
Abstract Glycine receptor chloride channels are Cys-loop receptor proteins that isomerize between a low affinity closed state and a high affinity ion-conducting state. There is currently much interest in understanding the mechanisms that link affinity changes with conductance changes. This essentially involves an agonist binding in the glycine receptor ligand-binding site initiating local conformational changes that propagate in a wave towards the channel gate. However, it has proved difficult to convincingly distinguish those agonist-induced domain movements that are critical for triggering activation from those that are simply local deformations to accommodate ligands in the site. We employed voltage-clamp fluorometry to compare conformational changes in the ligand-binding site in response to activation by glycine, which binds locally, and ivermectin, which binds in the transmembrane domain. We reasoned that ivermectin-mediated activation should initiate a conformational wave that propagates from the pore-lining domain towards the ligand-binding domain, eliciting conformational changes in those extracellular domains that are allosterically linked to the gate. We found that ivermectin indeed elicited conformational changes in ligand-binding domain loops C, D and F. This implies that conformational changes in these domains are important for activation. This result also provides a mechanism to explain how ivermectin potentiates glycine-induced channel activation.
Keyword Ivermectin
Cys-loop receptor
Gating
Electrophysiology
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 11 November 2011

 
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Created: Mon, 12 Mar 2012, 16:38:34 EST by Debra McMurtrie on behalf of Queensland Brain Institute