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 NMDA ionotropic glutamate receptor is ubiquitous in mammalian central neurons. Because partial agonists bind to the same site as glutamate but induce less channel activation, these compounds provide an opportunity to probe the mechanism of activation of NMDA-type glutamate receptors. Molecular dynamics simulations and site-directed mutagenesis demonstrate that the partial agonist homoquinolinate interacts differently with binding pocket residues than glutamate. Homoquinolinate and glutamate induce distinct changes in the binding pocket, and the binding pocket exhibits significantly more motion with homoquinolinate bound than with glutamate. Patch-clamp recording demonstrates that single-channel activity induced by glutamate or by homoquinolinate has identical single-channel current amplitude and mean open-channel duration but that homoquinolinate slows activation of channel opening relative to glutamate. We hypothesize that agonist-induced conformational changes in the binding pocket control the efficacy of a subunit-specific activation step that precedes the concerted global change in the receptor-channel complex associated with ion channel opening.
ARIENS,
Affinity and intrinsic activity in the theory of competitive inhibition. I. Problems and theory.
1954, Pubmed
ARIENS,
Affinity and intrinsic activity in the theory of competitive inhibition. I. Problems and theory.
1954,
Pubmed Armstrong,
Structure of a glutamate-receptor ligand-binding core in complex with kainate.
1998,
Pubmed Armstrong,
Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core.
2000,
Pubmed Banke,
Protons trap NR1/NR2B NMDA receptors in a nonconducting state.
2005,
Pubmed Banke,
Activation of NR1/NR2B NMDA receptors.
2003,
Pubmed 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 DEL CASTILLO,
Interaction at end-plate receptors between different choline derivatives.
1957,
Pubmed Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed Erreger,
Glutamate receptor gating.
2004,
Pubmed Erreger,
Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles.
2005,
Pubmed Furukawa,
Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core.
2003,
Pubmed Gibb,
Glutamate activation of a single NMDA receptor-channel produces a cluster of channel openings.
1991,
Pubmed Gouaux,
Structure and function of AMPA receptors.
2004,
Pubmed Inanobe,
Mechanism of partial agonist action at the NR1 subunit of NMDA receptors.
2005,
Pubmed
,
Xenbase Jackson,
Successive openings of the same acetylcholine receptor channel are correlated in open time.
1983,
Pubmed Jin,
Probing the function, conformational plasticity, and dimer-dimer contacts of the GluR2 ligand-binding core: studies of 5-substituted willardiines and GluR2 S1S2 in the crystal.
2003,
Pubmed Jin,
Structural basis for partial agonist action at ionotropic glutamate receptors.
2003,
Pubmed
,
Xenbase Jin,
Mechanism of activation and selectivity in a ligand-gated ion channel: structural and functional studies of GluR2 and quisqualate.
2002,
Pubmed
,
Xenbase Mayer,
Structure and function of glutamate receptor ion channels.
2004,
Pubmed Popescu,
Modal gating of NMDA receptors and the shape of their synaptic response.
2003,
Pubmed Popescu,
Reaction mechanism determines NMDA receptor response to repetitive stimulation.
2004,
Pubmed Qin,
Estimating single-channel kinetic parameters from idealized patch-clamp data containing missed events.
1996,
Pubmed
,
Xenbase Qin,
Restoration of single-channel currents using the segmental k-means method based on hidden Markov modeling.
2004,
Pubmed Rosenmund,
The tetrameric structure of a glutamate receptor channel.
1998,
Pubmed Smith,
Heterogeneous conductance levels of native AMPA receptors.
2000,
Pubmed STEPHENSON,
A modification of receptor theory.
1956,
Pubmed Traynelis,
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
1998,
Pubmed
,
Xenbase Wyllie,
Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors.
1998,
Pubmed
,
Xenbase Zheng,
Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition.
1998,
Pubmed Zheng,
Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A.
2001,
Pubmed
