Phosphorylation of α3 glycine receptors induces a conformational change in the glycine-binding site

Han, Lu, Talwar, Sahil, Wang, Qian, Shan, Qiang and Lynch, Joseph W. (2013) Phosphorylation of α3 glycine receptors induces a conformational change in the glycine-binding site. ACS Chemical Neuroscience, 4 10: 1361-1370. doi:10.1021/cn400097j

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads
UQ318125_postprint.pdf Full text (open access) application/pdf 1.58MB 22

Author Han, Lu
Talwar, Sahil
Wang, Qian
Shan, Qiang
Lynch, Joseph W.
Title Phosphorylation of α3 glycine receptors induces a conformational change in the glycine-binding site
Journal name ACS Chemical Neuroscience   Check publisher's open access policy
ISSN 1948-7193
Publication date 2013-10-16
Year available 2013
Sub-type Article (original research)
DOI 10.1021/cn400097j
Open Access Status File (Author Post-print)
Volume 4
Issue 10
Start page 1361
End page 1370
Total pages 10
Place of publication Washington, DC United States
Publisher American Chemical Society
Collection year 2014
Language eng
Subject 1303 Specialist Studies in Education
1307 Cell Biology
1314 Physiology
2805 Cognitive Neuroscience
Abstract Inflammatory pain sensitization is initiated by prostaglandin-induced phosphorylation of α3 glycine receptors (GlyRs) that are specifically located in inhibitory synapses on spinal pain sensory neurons. Phosphorylation reduces the magnitude of glycinergic synaptic currents, thereby disinhibiting nociceptive neurons. Although α1 and α3 subunits are both expressed on spinal nociceptive neurons, α3 is a more promising therapeutic target as its sparse expression elsewhere implies a reduced risk of side-effects. Here we compared glycine-mediated conformational changes in α1 and α3 GlyRs to identify structural differences that might be exploited in designing α3-specific analgesics. Using voltage-clamp fluorometry, we show that glycine-mediated conformational changes in the extracellular M2-M3 domain were significantly different between the two GlyR isoforms. Using a chimeric approach, we found that structural variations in the intracellular M3-M4 domain were responsible for this difference. This prompted us to test the hypothesis that phosphorylation of S346 in α3 GlyR might also induce extracellular conformation changes. We show using both voltage-clamp fluorometry and pharmacology that Ser346 phosphorylation elicits structural changes in the α3 glycine-binding site. These results provide the first direct evidence for phosphorylation-mediated extracellular conformational changes in pentameric ligand-gated ion channels, and thus suggest new loci for investigating how phosphorylation modulates structure and function in this receptor family. More importantly, by demonstrating that phosphorylation alters α3 GlyR glycine-binding site structure, they raise the possibility of developing analgesics that selectively target inflammation-modulated GlyRs.
Keyword Cys Loop Receptors
Glycinergic synapse
Inflammatory Pain
Protein Conformation
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
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 14 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 28 Nov 2013, 20:42:42 EST by System User on behalf of Queensland Brain Institute