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J Biol Chem
2008 Aug 01;28331:21519-29. doi: 10.1074/jbc.M709190200.
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Constitutive activation of the N-methyl-D-aspartate receptor via cleft-spanning disulfide bonds.
Blanke ML
,
VanDongen AM
.
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Although the N-methyl-D-aspartate (NMDA) receptor plays a critical role in the central nervous system, many questions remain regarding the relationship between its structure and functional properties. In particular, the involvement of ligand-binding domain closure in determining agonist efficacy, which has been reported in other glutamate receptor subtypes, remains unresolved. To address this question, we designed dual cysteine point mutations spanning the NR1 and NR2 ligand-binding clefts, aiming to stabilize these domains in closed cleft conformations. Two mutants, E522C/I691C in NR1 (EI) and K487C/N687C in NR2 (KN) were found to exhibit significant glycine- and glutamate-independent activation, respectively, and co-expression of the two subunits produced a constitutively active channel. However, both individual mutants could be activated above constitutive levels in a concentration-dependent manner, indicating that cleft closure does not completely prevent agonist association. Interestingly, whereas the NR2 KN disulfide was found to potentiate channel gating and M3 accessibility, NR1 EI exhibited the opposite phenotype, suggesting that the EI disulfide may trap the NR1 ligand-binding domain in a lower efficacy conformation. Furthermore, both mutants affected agonist sensitivity at the opposing subunit, suggesting that closed cleft stabilization may contribute to coupling between the subunits. These results support a correlation between cleft stability and receptor activation, providing compelling evidence for the Venus flytrap mechanism of glutamate receptor domain closure.
Arinaminpathy,
Molecular dynamics simulations of the ligand-binding domain of the ionotropic glutamate receptor GluR2.
2002, Pubmed
Arinaminpathy,
Molecular dynamics simulations of the ligand-binding domain of the ionotropic glutamate receptor GluR2.
2002,
Pubmed
Armstrong,
Tuning activation of the AMPA-sensitive GluR2 ion channel by genetic adjustment of agonist-induced conformational changes.
2003,
Pubmed
,
Xenbase
Armstrong,
Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core.
2000,
Pubmed
Armstrong,
Structure of a glutamate-receptor ligand-binding core in complex with kainate.
1998,
Pubmed
Banke,
Protons trap NR1/NR2B NMDA receptors in a nonconducting state.
2005,
Pubmed
Bashir,
Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus.
1991,
Pubmed
Benveniste,
A kinetic analysis of the modulation of N-methyl-D-aspartic acid receptors by glycine in mouse cultured hippocampal neurones.
1990,
Pubmed
Chen,
Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes.
2008,
Pubmed
,
Xenbase
Chen,
Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling.
2005,
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
Emamian,
Decreased phosphorylation of NMDA receptor type 1 at serine 897 in brains of patients with Schizophrenia.
2004,
Pubmed
Erreger,
Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles.
2005,
Pubmed
Erreger,
Mechanism of partial agonism at NMDA receptors for a conformationally restricted glutamate analog.
2005,
Pubmed
,
Xenbase
Erreger,
Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors.
2007,
Pubmed
,
Xenbase
Furukawa,
Subunit arrangement and function in NMDA receptors.
2005,
Pubmed
Grosman,
The dissociation of acetylcholine from open nicotinic receptor channels.
2001,
Pubmed
Hansen,
Tweaking agonist efficacy at N-methyl-D-aspartate receptors by site-directed mutagenesis.
2005,
Pubmed
,
Xenbase
Hynd,
Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease.
2004,
Pubmed
Inanobe,
Mechanism of partial agonist action at the NR1 subunit of NMDA receptors.
2005,
Pubmed
,
Xenbase
Jin,
Structural basis for partial agonist action at ionotropic glutamate receptors.
2003,
Pubmed
,
Xenbase
Jones,
The NMDA receptor M3 segment is a conserved transduction element coupling ligand binding to channel opening.
2002,
Pubmed
,
Xenbase
Kalbaugh,
Ligand-binding residues integrate affinity and efficacy in the NMDA receptor.
2004,
Pubmed
,
Xenbase
Kauer,
NMDA application potentiates synaptic transmission in the hippocampus.
1988,
Pubmed
Kaye,
Molecular dynamics simulations of the ligand-binding domain of an N-methyl-D-aspartate receptor.
2006,
Pubmed
Kaye,
In silico mutation of cysteine residues in the ligand-binding domain of an N-methyl-D-aspartate receptor.
2007,
Pubmed
Kniazeff,
Locking the dimeric GABA(B) G-protein-coupled receptor in its active state.
2004,
Pubmed
Leonard,
Apparent desensitization of NMDA responses in Xenopus oocytes involves calcium-dependent chloride current.
1990,
Pubmed
,
Xenbase
Lerma,
Glycine decreases desensitization of N-methyl-D-aspartate (NMDA) receptors expressed in Xenopus oocytes and is required for NMDA responses.
1990,
Pubmed
,
Xenbase
Low,
Molecular determinants of proton-sensitive N-methyl-D-aspartate receptor gating.
2003,
Pubmed
,
Xenbase
Low,
Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors.
2000,
Pubmed
,
Xenbase
Maier,
Disruption of interdomain interactions in the glutamate binding pocket affects differentially agonist affinity and efficacy of N-methyl-D-aspartate receptor activation.
2007,
Pubmed
Mayer,
Crystal structures of the GluR5 and GluR6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity.
2005,
Pubmed
McFeeters,
Structural mobility of the extracellular ligand-binding core of an ionotropic glutamate receptor. Analysis of NMR relaxation dynamics.
2002,
Pubmed
Mody,
NMDA receptor-dependent excitotoxicity: the role of intracellular Ca2+ release.
1995,
Pubmed
Paoletti,
Molecular organization of a zinc binding n-terminal modulatory domain in a NMDA receptor subunit.
2000,
Pubmed
,
Xenbase
Regalado,
Intersubunit cooperativity in the NMDA receptor.
2001,
Pubmed
Robert,
AMPA receptor binding cleft mutations that alter affinity, efficacy, and recovery from desensitization.
2005,
Pubmed
Rosenmund,
Synaptic NMDA receptor channels have a low open probability.
1995,
Pubmed
Schorge,
Studies of NMDA receptor function and stoichiometry with truncated and tandem subunits.
2003,
Pubmed
Sheng,
Changing subunit composition of heteromeric NMDA receptors during development of rat cortex.
1994,
Pubmed
Tsai,
Improved cognition in Alzheimer's disease with short-term D-cycloserine treatment.
1999,
Pubmed
Weston,
Interdomain interactions in AMPA and kainate receptors regulate affinity for glutamate.
2006,
Pubmed
Wood,
Structural conservation of ion conduction pathways in K channels and glutamate receptors.
1995,
Pubmed
,
Xenbase
Wood,
The 5'-untranslated region of the N-methyl-D-aspartate receptor NR2A subunit controls efficiency of translation.
1996,
Pubmed
,
Xenbase
Yaka,
D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury.
2007,
Pubmed
Zhang,
Potentiation of NMDA receptor-mediated responses by dynorphin at low extracellular glycine concentrations.
1997,
Pubmed
,
Xenbase
Zheng,
Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A.
2001,
Pubmed
