Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2013 Oct 15;11042:17113-8. doi: 10.1073/pnas.1317009110.
Show Gene links
Show Anatomy links
Intermediate closed state for glycine receptor function revealed by cysteine cross-linking.
Prevost MS
,
Moraga-Cid G
,
Van Renterghem C
,
Edelstein SJ
,
Changeux JP
,
Corringer PJ
.
???displayArticle.abstract???
Pentameric ligand-gated ion channels (pLGICs) mediate signal transmission by coupling the binding of extracellular ligands to the opening of their ion channel. Agonist binding elicits activation and desensitization of pLGICs, through several conformational states, that are, thus far, incompletely characterized at the structural level. We previously reported for GLIC, a prokaryotic pLGIC, that cross-linking of a pair of cysteines at both sides of the extracellular and transmembrane domain interface stabilizes a locally closed (LC) X-ray structure. Here, we introduced the homologous pair of cysteines on the human α1 glycine receptor. We show by electrophysiology that cysteine cross-linking produces a gain-of-function phenotype characterized by concomitant constitutive openings, increased agonist potency, and equalization of efficacies of full and partial agonists. However, it also produces a reduction of maximal currents at saturating agonist concentrations without change of the unitary channel conductance, an effect reversed by the positive allosteric modulator propofol. The cross-linking thus favors a unique closed state distinct from the resting and longest-lived desensitized states. Fitting the data according to a three-state allosteric model suggests that it could correspond to a LC conformation. Its plausible assignment to a gating intermediate or a fast-desensitized state is discussed. Overall, our data show that relative movement of two loops at the extracellular-transmembrane interface accompanies orthosteric agonist-mediated gating.
Auerbach,
Desensitization of mouse nicotinic acetylcholine receptor channels. A two-gate mechanism.
1998, Pubmed
Auerbach,
Desensitization of mouse nicotinic acetylcholine receptor channels. A two-gate mechanism.
1998,
Pubmed
Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed
Burzomato,
Single-channel behavior of heteromeric alpha1beta glycine receptors: an attempt to detect a conformational change before the channel opens.
2004,
Pubmed
Colquhoun,
Perspectives on: conformational coupling in ion channels: allosteric coupling in ligand-gated ion channels.
2012,
Pubmed
Corringer,
Structure and pharmacology of pentameric receptor channels: from bacteria to brain.
2012,
Pubmed
Duret,
Functional prokaryotic-eukaryotic chimera from the pentameric ligand-gated ion channel family.
2011,
Pubmed
,
Xenbase
Edelstein,
A kinetic mechanism for nicotinic acetylcholine receptors based on multiple allosteric transitions.
1996,
Pubmed
Elenes,
Desensitization of diliganded mouse muscle nicotinic acetylcholine receptor channels.
2002,
Pubmed
Galzi,
The multiple phenotypes of allosteric receptor mutants.
1996,
Pubmed
Heidmann,
Structural and functional properties of the acetylcholine receptor protein in its purified and membrane-bound states.
1978,
Pubmed
Heidmann,
Interaction of a fluorescent agonist with the membrane-bound acetylcholine receptor from Torpedo marmorata in the millisecond time range: resolution of an "intermediate" conformational transition and evidence for positive cooperative effects.
1980,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Hilf,
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.
2009,
Pubmed
Keramidas,
An outline of desensitization in pentameric ligand-gated ion channel receptors.
2013,
Pubmed
Kirson,
Positive allosteric modulators differentially affect full versus partial agonist activation of the glycine receptor.
2012,
Pubmed
,
Xenbase
Lape,
On the nature of partial agonism in the nicotinic receptor superfamily.
2008,
Pubmed
Lape,
The α1K276E startle disease mutation reveals multiple intermediate states in the gating of glycine receptors.
2012,
Pubmed
Lobo,
Cross-linking of glycine receptor transmembrane segments two and three alters coupling of ligand binding with channel opening.
2004,
Pubmed
,
Xenbase
Lynch,
The surface accessibility of the glycine receptor M2-M3 loop is increased in the channel open state.
2001,
Pubmed
Lynch,
Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel.
1997,
Pubmed
MONOD,
ON THE NATURE OF ALLOSTERIC TRANSITIONS: A PLAUSIBLE MODEL.
1965,
Pubmed
Mukhtasimova,
Detection and trapping of intermediate states priming nicotinic receptor channel opening.
2009,
Pubmed
Neubig,
Permeability control by cholinergic receptors in Torpedo postsynaptic membranes: agonist dose-response relations measured at second and millisecond times.
1980,
Pubmed
Parikh,
Structure of the M2 transmembrane segment of GLIC, a prokaryotic Cys loop receptor homologue from Gloeobacter violaceus, probed by substituted cysteine accessibility.
2011,
Pubmed
Perkins,
Loop 2 structure in glycine and GABA(A) receptors plays a key role in determining ethanol sensitivity.
2009,
Pubmed
,
Xenbase
Pless,
Conformational variability of the glycine receptor M2 domain in response to activation by different agonists.
2007,
Pubmed
,
Xenbase
Prevost,
A locally closed conformation of a bacterial pentameric proton-gated ion channel.
2012,
Pubmed
Purohit,
A stepwise mechanism for acetylcholine receptor channel gating.
2007,
Pubmed
Sakmann,
Single acetylcholine-activated channels show burst-kinetics in presence of desensitizing concentrations of agonist.
1980,
Pubmed
Sauguet,
Structural basis for ion permeation mechanism in pentameric ligand-gated ion channels.
2013,
Pubmed
,
Xenbase
Schmieden,
Pharmacology of the inhibitory glycine receptor: agonist and antagonist actions of amino acids and piperidine carboxylic acid compounds.
1995,
Pubmed
,
Xenbase
Velisetty,
Conformational transitions underlying pore opening and desensitization in membrane-embedded Gloeobacter violaceus ligand-gated ion channel (GLIC).
2012,
Pubmed
Yamodo,
Conformational changes in the nicotinic acetylcholine receptor during gating and desensitization.
2010,
Pubmed