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Journal of Medicinal Chemistry, 2002
We present new homology-based models of the glutamate binding site (in closed and open forms) of the NMDA receptor NR2B subunit derived from X-ray structures of the water soluble AMPA sensitive glutamate receptor. The models were used for revealing binding modes of agonists and competitive antagonists, as well as for rationalizing known experimental facts concerning structure-activity relationships: (i) the switching between the agonist and the antagonist modes of action upon lengthening the chain between the distal acidic group and the amino acid moiety, (ii) the preference for the methyl group attached to the R-amino group of ligands, (iii) the preference for the D-configuration of agonists and antagonists, and (iv) the existence of "superacidic" agonists.
Partial Agonists and Subunit Selectivity at NMDA Receptors
Chemistry - A European Journal, 2010
Figure 1. Glutamate receptors are divided into iontropic and metabotropic receptors. These two families are further subdivided into three classes: NMDA, AMPA, and KA for ionotropic receptors and I-III for metabotropic receptors. Each class contains several cloned subunits that assemble as tetramers for ionotropic receptors and dimers for metabotropic receptors. Scheme 1. Structures of AMPA (1), kainic acid (2), NMDA (3), and glutamate (4). Scheme 2. Structures of Cl-HIBO (5), 2-Bn-tet-AMPA (6), and 8-Me-4-AHCP (7).
Neuron, 1997
stimulation resulting in high Ca 2ϩ influx causes neuronal cell death in ischemia and other neurodegenerative dis-Heinrich Betz, and Jochen Kuhse orders (Choi, 1988). Third, simultaneous binding of glu-Department of Neurochemistry tamate and the coagonist glycine is required for efficient Max-Planck-Institute for Brain Research activation of NMDA receptors (Johnson and Ascher, Deutschordenstrae 46 1987; Kleckner and Dingledine, 1988). The mechanism 60528 Frankfurt of coagonist action is not entirely clear but may involve Federal Republic of Germany allosteric modulation of agonist binding affinities (Mayer *Symphony Pharmaceuticals Inc. et al., 1989). Pharmacological and electrophysiological Frazer, Pennsylvania 19355 studies indicate that glutamate and glycine occupy distinct sites of the receptor protein (Reynolds et al., 1987; Henderson et al., 1990). Summary Molecular studies have shown that NMDA receptors are oligomeric membrane proteins composed of homol-NMDA receptors require both L-glutamate and the coogous NMDAR1 (NR1) and NR2 subunits (reviewed by agonist glycine for efficient channel activation. The Hollmann and Heinemann, 1994). The NR1 and NR2 subglycine binding site of these heteromeric receptor prounits are synthesized as precursor proteins with a cleavteins is formed by regions of the NMDAR1 (NR1) subable leader sequence followed by a long N-terminal unit that display sequence similarity to bacterial amino extracellular domain and, in the second half of the polyacid binding proteins. Here, we demonstrate that the peptides, four hydrophobic membrane segments (M1glutamate binding site is located on the homologous M4). The M1, M3, and M4 segments are transmembrane regions of the NR2B subunit. Mutation of residues spanning, whereas segment M2 is thought to form a within the N-terminal domain and the loop region bereentrant loop (Hollmann and Heinemann, 1994; Bennett tween membrane segments M3 and M4 significantly and Dingledine, 1995; Wo and Oswald, 1994; Hirai et al., reduced the efficacy of glutamate, but not glycine, in 1996) that lines the ion channel (Kuner et al., 1996). channel gating. Some of the mutations also decreased The NR1 subunit is expressed in several distinct splice inhibition by the glutamate antagonists, D-AP5 and variants throughout the central nervous system (Durand R-CPP. Homology-based molecular modeling of the et al., 1992; Nakanishi et al., 1992; Sugihara et al., 1992; glutamate and glycine binding domains indicates that Hollmann et al., 1993). The NR2 subunit exists in four the NR2 and NR1 subunits use similar residues to liisoforms encoded by different genes (NR2A-D), which gate the agonists' ␣-aminocarboxylic acid groups, create further functional and regional heterogeneity of whereas differences in side chain interactions and size NMDA receptors (Kutsuwada et al., 1992; Meguro et al., of aromatic residues determine ligand selectivity. 1992; Monyer et al., 1992). Heterologous expression in Xenopus laevis oocytes has suggested that the NR1
Molecular Pharmacology, 2013
N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We used a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. Using two-electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single-channel recordings, we show that propyl-and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (,1-72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits.
Molecular Pharmacology, 2013
N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We used a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. Using two-electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single-channel recordings, we show that propyl-and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (,1-72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits.
Structural determinants of the blocker binding site in glutamate and NMDA receptor channels
Neuropharmacology, 1998
Glutamate receptor channels of the NMDA-type (N-methyl-D-aspartate) and non-NMDA-type (GluR) differ in their pore properties. The N-site in the M2 transmembrane segment of NMDA receptors (NMDAR), or the corresponding Q/R-site in GluRs, is a pivotal structural determinant of their permeation and blockade characteristics. Substitutions at a second site in M2, the L-site (L577) in GluR1, drastically alter the receptor selectivity to divalent cations. Here we report that M2 mutants carrying an asparagine or a threonine residue at the Q-site of GluR1, along with a tryptophan residue at the L-site, form homomeric GluR1 channels that are highly sensitive to structurally diverse, uncompetitive NMDA antagonists such as arylcyclohexylamines, dibenzocycloheptenimines, and to morphinian and adamantane derivatives. Analysis of the voltage dependence of channel blockade locates the blocker binding site 0.65 partway into the transmembrane electric field in both GluR1 mutants and NMDAR channels. Our results suggest that the homomeric GluR1 double mutants, L577W/Q582N and L577W/Q582T, fairly approximate the pore properties of the heteromeric NMDA receptor and support the structural kinship of their permeation pathways.
Structure, function, and allosteric modulation of NMDA receptors
Journal of General Physiology, 2018
NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin t...
F1000 - Post-publication peer review of the biomedical literature
NMDA receptors are ligand-gated ion channels that underlie transmission at excitatory synapses and play an important role in regulating synaptic strength and stability. Functional NMDA receptors require two copies of the GluN1 subunit coassembled with GluN2 (and/or GluN3) subunits into a heteromeric tetramer. A diverse array of allosteric modulators can upregulate or downregulate NMDA receptor activity. These modulators include both synthetic compounds and endogenous modulators, such as cis-unsaturated fatty acids, 24(S)hydroxycholesterol, and various neurosteroids. To evaluate the structural requirements for the formation and allosteric modulation of NMDA receptor pores, we have replaced portions of the rat GluN1, GluN2A, and GluN2B subunits with homologous segments from the rat GluK2 kainate receptor subunit. Our results with these chimeric constructs show that the NMDA receptor transmembrane domain is sufficient to account for most pore properties, but that regulation by some allosteric modulators requires additional cytoplasmic or extracellular domains.
A structurally derived model of subunit-dependent NMDA receptor function
The Journal of Physiology
The kinetics of NMDA receptor (NMDAR) signalling are a critical aspect of the physiology of excitatory synaptic transmission in the brain. r Here we develop a mechanistic description of NMDAR function based on the receptor tetrameric structure and the principle that each agonist-bound subunit must undergo some rate-limiting conformational change after agonist binding, prior to channel opening. r By fitting this mechanism to single channel data using a new MATLAB-based software implementation of maximum likelihood fitting with correction for limited time resolution, rate constants were derived for this mechanism that reflect distinct structural changes and predict the properties of macroscopic and synaptic NMDAR currents. r The principles applied here to develop a mechanistic description of the heterotetrameric NMDAR, and the software used in this analysis, can be equally applied to other heterotetrameric glutamate receptors, providing a unifying mechanistic framework to understanding the physiology of glutamate receptor signalling in the brain.