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ACS Chem Neurosci
2013 Oct 16;410:1361-70. doi: 10.1021/cn400097j.
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Phosphorylation of α3 glycine receptors induces a conformational change in the glycine-binding site.
Han L
,
Talwar S
,
Wang Q
,
Shan Q
,
Lynch JW
.
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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.
Abramian,
Protein kinase C phosphorylation regulates membrane insertion of GABAA receptor subtypes that mediate tonic inhibition.
2010, Pubmed
Abramian,
Protein kinase C phosphorylation regulates membrane insertion of GABAA receptor subtypes that mediate tonic inhibition.
2010,
Pubmed
Ahmadi,
PGE(2) selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons.
2002,
Pubmed
Balansa,
Ircinialactams: subunit-selective glycine receptor modulators from Australian sponges of the family Irciniidae.
2010,
Pubmed
Bourne,
Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors.
2005,
Pubmed
Celie,
Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an alpha-conotoxin PnIA variant.
2005,
Pubmed
,
Xenbase
Chen,
Molecular determinants of beta-carboline inhibition of the glycine receptor.
2009,
Pubmed
Dahan,
A fluorophore attached to nicotinic acetylcholine receptor beta M2 detects productive binding of agonist to the alpha delta site.
2004,
Pubmed
,
Xenbase
Han,
Comparison of taurine- and glycine-induced conformational changes in the M2-M3 domain of the glycine receptor.
2004,
Pubmed
Han,
The relative orientation of the TM3 and TM4 domains varies between α1 and α3 glycine receptors.
2013,
Pubmed
,
Xenbase
Harvey,
GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization.
2004,
Pubmed
Houston,
CaMK-II modulation of GABA(A) receptors expressed in HEK293, NG108-15 and rat cerebellar granule neurons.
2006,
Pubmed
Huang,
Mechanisms of homomeric alpha1 glycine receptor endocytosis.
2007,
Pubmed
Legendre,
The glycinergic inhibitory synapse.
2001,
Pubmed
Lynagh,
An improved ivermectin-activated chloride channel receptor for inhibiting electrical activity in defined neuronal populations.
2010,
Pubmed
Lynch,
Molecular structure and function of the glycine receptor chloride channel.
2004,
Pubmed
Lynch,
Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel.
1997,
Pubmed
Lynch,
Glycine receptors: a new therapeutic target in pain pathways.
2006,
Pubmed
Lynch,
The surface accessibility of the glycine receptor M2-M3 loop is increased in the channel open state.
2001,
Pubmed
Maksay,
Different binding modes of tropeines mediating inhibition and potentiation of alpha1 glycine receptors.
2009,
Pubmed
,
Xenbase
Manzke,
Serotonin receptor 1A-modulated phosphorylation of glycine receptor α3 controls breathing in mice.
2010,
Pubmed
McDonald,
Adjacent phosphorylation sites on GABAA receptor beta subunits determine regulation by cAMP-dependent protein kinase.
1998,
Pubmed
Miller,
Binding, activation and modulation of Cys-loop receptors.
2010,
Pubmed
Pless,
Conformational variability of the glycine receptor M2 domain in response to activation by different agonists.
2007,
Pubmed
,
Xenbase
Pless,
Ligand-specific conformational changes in the alpha1 glycine receptor ligand-binding domain.
2009,
Pubmed
,
Xenbase
Rajendra,
The unique extracellular disulfide loop of the glycine receptor is a principal ligand binding element.
1995,
Pubmed
Saliba,
Activity-dependent phosphorylation of GABAA receptors regulates receptor insertion and tonic current.
2012,
Pubmed
Shan,
Ivermectin, an unconventional agonist of the glycine receptor chloride channel.
2001,
Pubmed
Shan,
Chimera construction using multiple-template-based sequential PCRs.
2010,
Pubmed
Swope,
Regulation of ligand-gated ion channels by protein phosphorylation.
1999,
Pubmed
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Velázquez-Flores,
Glycine receptor internalization by protein kinases activation.
2011,
Pubmed
Wang,
Activation and desensitization induce distinct conformational changes at the extracellular-transmembrane domain interface of the glycine receptor.
2011,
Pubmed
,
Xenbase
Webb,
Molecular pharmacology of the glycine receptor chloride channel.
2007,
Pubmed
Xiong,
Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors.
2012,
Pubmed
Yakel,
Activation and desensitization of the 5-HT3 receptor in a rat glioma x mouse neuroblastoma hybrid cell.
1991,
Pubmed
Yang,
Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition.
2007,
Pubmed
Zeilhofer,
The glycinergic control of spinal pain processing.
2005,
Pubmed
