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.
???displayArticle.abstract???
The glycine receptor (GlyR) exists either in homomeric α or heteromeric αβ forms. Its agonists bind at extracellular subunit interfaces. Unlike subunit interfaces from the homomeric α GlyR, subunit interfaces from the heteromeric αβ GlyR have not been characterized unambiguously because of the existence of multiple types of interface within single receptors. Here, we report that, by reconstituting β+/α- interfaces in a homomeric GlyR (αChb+a- GlyR), we were able to functionally characterize the αβ GlyR β+/α- interfaces. We found that the β+/α- interface had a higher agonist sensitivity than that of the α+/α- interface. This high sensitivity was contributed primarily by loop A. We also found that the β+/α- interface differentially modulates the agonist properties of glycine and taurine. Using voltage clamp fluorometry, we found that the conformational changes induced by glycine binding to the β+/α- interface were different from those induced by glycine binding to the α+/α- interface in the α GlyR. Moreover, the distinct conformational changes found at the β+/α- interface in the αChb+a- GlyR were also found in the heteromeric αβ GlyR, which suggests that the αChb+a- GlyR reconstitutes structural components and recapitulates functional properties, of the β+/α- interface in the heteromeric αβ GlyR. Our investigation not only provides structural and functional information about the GlyR β+/α- interface, which could direct GlyR β+/α- interface-specific drug design, but also provides a general methodology for unambiguously characterizing properties of specific protein interfaces from heteromeric proteins.
Barnes,
The 5-HT3 receptor--the relationship between structure and function.
2009, Pubmed
Barnes,
The 5-HT3 receptor--the relationship between structure and function.
2009,
Pubmed Blount,
Molecular basis of the two nonequivalent ligand binding sites of the muscle nicotinic acetylcholine receptor.
1989,
Pubmed Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed Bouzat,
Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel.
2004,
Pubmed Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed Buhr,
Point mutations of the alpha 1 beta 2 gamma 2 gamma-aminobutyric acid(A) receptor affecting modulation of the channel by ligands of the benzodiazepine binding site.
1996,
Pubmed
,
Xenbase Colquhoun,
Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
1998,
Pubmed Duncalfe,
The major site of photoaffinity labeling of the gamma-aminobutyric acid type A receptor by [3H]flunitrazepam is histidine 102 of the alpha subunit.
1996,
Pubmed Gandhi,
Shedding light on membrane proteins.
2005,
Pubmed Grudzinska,
The beta subunit determines the ligand binding properties of synaptic glycine receptors.
2005,
Pubmed Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed Hilf,
X-ray structure of a prokaryotic pentameric ligand-gated ion channel.
2008,
Pubmed Hilf,
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.
2009,
Pubmed Karlin,
Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins.
1995,
Pubmed Kucken,
Identification of benzodiazepine binding site residues in the gamma2 subunit of the gamma-aminobutyric acid(A) receptor.
2000,
Pubmed Lee,
Binding to gating transduction in nicotinic receptors: Cys-loop energetically couples to pre-M1 and M2-M3 regions.
2009,
Pubmed Lewis,
Kinetic determinants of agonist action at the recombinant human glycine receptor.
2003,
Pubmed Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase Lummis,
Cis-trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel.
2005,
Pubmed Lynagh,
Molecular determinants of ivermectin sensitivity at the glycine receptor chloride channel.
2011,
Pubmed Lynch,
Molecular structure and function of the glycine receptor chloride channel.
2004,
Pubmed Lynch,
Native glycine receptor subtypes and their physiological roles.
2009,
Pubmed Lynch,
The surface accessibility of the glycine receptor M2-M3 loop is increased in the channel open state.
2001,
Pubmed Miller,
Binding, activation and modulation of Cys-loop receptors.
2010,
Pubmed Olsen,
GABA A receptors: subtypes provide diversity of function and pharmacology.
2009,
Pubmed Olsen,
International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update.
2008,
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 Pless,
Illuminating the structure and function of Cys-loop receptors.
2008,
Pubmed Pless,
Magnitude of a conformational change in the glycine receptor beta1-beta2 loop is correlated with agonist efficacy.
2009,
Pubmed Ramerstorfer,
The GABAA receptor alpha+beta- interface: a novel target for subtype selective drugs.
2011,
Pubmed
,
Xenbase Shan,
A single beta subunit M2 domain residue controls the picrotoxin sensitivity of alphabeta heteromeric glycine receptor chloride channels.
2001,
Pubmed Shan,
Chimera construction using multiple-template-based sequential PCRs.
2010,
Pubmed Shan,
β Subunit M2-M3 loop conformational changes are uncoupled from α1 β glycine receptor channel gating: implications for human hereditary hyperekplexia.
2011,
Pubmed
,
Xenbase Shan,
Function of hyperekplexia-causing α1R271Q/L glycine receptors is restored by shifting the affected residue out of the allosteric signalling pathway.
2012,
Pubmed
,
Xenbase Sieghart,
A novel GABA(A) receptor pharmacology: drugs interacting with the α(+) β(-) interface.
2012,
Pubmed Sine,
Gamma- and delta-subunits regulate the affinity and the cooperativity of ligand binding to the acetylcholine receptor.
1991,
Pubmed Taly,
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.
2009,
Pubmed Thompson,
The structural basis of function in Cys-loop receptors.
2010,
Pubmed Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed Vogel,
Mapping of disulfide bonds within the amino-terminal extracellular domain of the inhibitory glycine receptor.
2009,
Pubmed
