Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Earlier studies have suggested that glutamate may play an important role in the transition between the mitotic (vegetative) and meiotic (sporulative) stages of the life cycle in the yeast Saccharomyces cerevisiae. Glutamate is also a major excitatory neurotransmitter in the vertebrate brain, and its actions are mediated by the excitatory amino acid (EAA) family of receptors, the three best-characterized of which are the N-methyl-D-aspartate (NMDA), quisqualate (Q), and kainate (K) receptors. As an initial test of the possibility that glutamate action in S. cerevisiae might be mediated by an EAA-like receptor mechanism, the effects of ligands that define the functional domains of the vertebrate NMDA receptor have been examined. The responses of S. cerevisiae cells to ligands that act at four distinct sites on the NMDA receptor provide the first evidence for an NMDA-like receptor-mediated system involved in the control of yeast sporulation.
Mol Microbiol 1990 Oct
PMID:Effects of N-methyl-D-aspartate receptor ligands on yeast sporulation. 198 4

Huntington's disease (HD) is an inherited neuropsychiatric degenerative process characterized by movement disorder, dementia, and, often, affective disorder (AfD) (seen in 38% of patients). Depression in HD is not just an understandable reaction to fatal illness: 10% of HD patients develop mania; AfD can occur 20 yr before neurological signs; and mood disorders are not randomly distributed, but occur in a subset of HD families. This evidence suggests that AfD in HD relates to brain pathophysiology. With its clear neuropathology, HD is proposed as one model for biological underpinnings of idiopathic AfD. There is striking atrophy and neuronal loss in HD neostriatum, particularly caudate. Caudate has rich connections to the limbic system. It is hypothesized that AfD in HD relates to dysfunction of the part of the neostriatum damaged earliest, dorsal medial caudate. Preliminary studies on neuropathological differences between HD patients with and without AfD are discussed. HD neurochemistry is reviewed, emphasizing the excitotoxin hypothesis, which involves dysfunction of the glutamate neurotransmitter system in HD (especially the NMDA receptor, which contains a channel with a phencyclidine (PCP) binding site). Based on the HD model, it is suggested that the glutamate system (particularly NMDA receptors) be examined in idiopathic AfD.
Mol Chem Neuropathol 1990 Mar
PMID:Huntington's disease as a model for mood disorders. Clues from neuropathology and neurochemistry. 214 28

The effect of phospholipase C (PLC) treatment of rat brain membranes on the binding properties of excitatory amino acid receptors was investigated using both a phosphsphatidylcholine-hydrolyzing PLC from Clostridium perfringens and a phosphatidylinositol-specific PLC from Bacillus thuringiensis. PLC from C. perfringens produced an increased affinity of the quisqualate/DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor for its ligand, whereas kainate receptor binding was not affected. Both kinetic analysis and equilibrium saturation experiments indicated that PLC treatment produced a decrease in affinity for [3H]N-(1-[thienyl]cyclohexyl)-piperidine [( 3H]TCP), a ligand for the N-methyl-D-aspartate (NMDA) receptor-associated ionic channel, when the channel was fully activated by high concentrations of glutamate and glycine but increased its binding under conditions in which the channel was presumably closed. This latter component of the binding was not due to an interaction of [3H]TCP with non-glutamate receptor sites, such as sigma opioid and histamine H3 receptors. Binding of [3H]glutamate and [3H] glycine to the NMDA receptors was not modified by PLC treatment, but there was a large decrease in the binding of the NMDA antagonist [3H]3-[(+/-)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid. Stimulation by glycine of [3H]glutamate binding was also abolished following PLC treatment. In contrast to PLC from C. perfringens, phosphatidylinositol-specific PLC treatment did not detectably modify the binding properties of the quisqualate/AMPA receptor or the NMDA receptor channel. These data indicate that alterations in the lipid microenvironment of the glutamate receptors modulate both the conformation and the function of the receptors and suggest a possible role for phospholipases in the regulation of synaptic transmission at excitatory synapses.
Mol Pharmacol 1990 Feb
PMID:N-Methyl-D-aspartate and quisqualate/DL-alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptors: differential regulation by phospholipase C treatment. 215 75

N-Methyl-D-aspartate (NMDA) receptors mediate important physiological and pathological processes, including long term potentiation and neuronal excitotoxicity. Elucidation of mechanisms underlying NMDA receptor functioning will promote understanding of the molecular bases of NMDA receptor-mediated processes. The localization of the phencyclidine (PCP) receptor within the ionophore of the NMDA receptor-gated ion channel permits the binding of PCP receptor ligands to serve as a functional marker of channel activation. We have previously demonstrated that the highly selective PCP receptor ligand [3H]MK-801 displays multiexponential kinetics of association, indicating that the NMDA receptor functions according to a multistate model. Using the fast component of [3H]MK-801 binding to PCP receptors as a marker for activated NMDA channels, we demonstrate here a Hill coefficient of 2 for activation of NMDA channels by L-glutamate. A multistate model of NMDA receptor functioning analogous to the model known to account for the functioning of nicotinic cholinergic and gamma-aminobutyric acidA receptors fits well to our experimental data, supporting the concept that the NMDA receptor is properly classified in the Class 1 superfamily of ligand-gated channels.
Mol Pharmacol 1990 May
PMID:Rat brain N-methyl-D-aspartate receptors require multiple molecules of agonist for activation. 216 56

The competitive N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate and two other five-atom linkage (C-5) omega-phosphono-alpha-amino acid analogs reduced [3H]glycine binding, in a dose-dependent manner, to a maximum of 45-55%, whereas seven-atom linkage (C-7) analogs had significantly less effect. The IC50 of the C-5 antagonists for the inhibition of [3H]glycine binding closely paralleled their potency both in displacing NMDA-selective L-[3H]glutamate binding and in negatively modulating (+)-[3H]5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne maleate ([3H]MK-801) binding. Additionally, reduction of glycine binding by the C-5 antagonists was reversed by both NMDA receptor agonists and C-7 competitive NMDA antagonists, providing evidence that the site of action of these C-5 antagonists is the NMDA recognition site, resulting in indirect modulation of the glycine site. These data imply a functional coupling between the NMDA and associated glycine recognition sites and, furthermore, suggest a differential interaction of C-5 and C-7 competitive NMDA antagonists with the NMDA receptor complex.
Mol Pharmacol 1990 Jun
PMID:Differential modulation of the associated glycine recognition site by competitive N-methyl-D-aspartate receptor antagonists. 216 12

5,7-Dichlorokynurenic acid (5,7-DCKA), one of the most potent excitatory amino acid receptor antagonists yet described, binds to a strychnine-insensitive glycine binding site located on the N-methyl-D-aspartate (NMDA) receptor complex (Ki = 79 nM versus [3H]glycine). 5,7-DCKA (10 microM) antagonized the ability of NMDA to stimulate the binding of the radiolabeled ion channel blocker N-[3H][1-(2-thienyl)cyclohexyl]-piperidine ([3]TCP). Glycine was able to overcome this effect and in the presence of 5,7-DCKA enhanced [3H]TCP binding to antagonist-free levels. 5,7-DCKA completely and noncompetitively antagonized several NMDA receptor-mediated biochemical and electrophysiological responses. Thus, micromolar concentrations of 5,7-DCKA inhibited NMDA-stimulated elevation of cytosolic calcium in cultured hippocampal neurons, cGMP accumulation in cerebellar slices, and norepinephrine release from hippocampal slices. The glycine antagonist could also block the action of synaptically released agonist, as shown by its ability to inhibit the increase in the magnitude of the population spike that follows tetanic stimulation of the hippocampus in vitro (long term potentiation). Inclusion of glycine or D-serine prevented all these effects of the antagonist. 5,7-DCKA was a potent anticonvulsant when administered intracerebroventricularly to mice. As in the in vitro experiments, the dose-response curve for the antagonist was shifted rightward in a parallel fashion when D-serine was coinjected. This spectrum of activity displayed by a compound acting at the glycine binding site suggests that the therapeutic utility of glycine antagonists will be similar to those proposed for other types of glutamate receptor antagonists.
Mol Pharmacol 1990 Oct
PMID:Activity of 5,7-dichlorokynurenic acid, a potent antagonist at the N-methyl-D-aspartate receptor-associated glycine binding site. 217 69

Phencyclidine (PCP) binds with high affinity to the ion channel associated with the NMDA receptor. The binding of the PCP receptor-specific ligand TCP is greatly reduced at temperatures between 2 degrees C and 6 degrees C, at which the plasma membrane is in a rigid state. However, membrane rigidity alone does not appear to cause the reduced TCP binding, since the membrane fluidizing agent A2C did not increase TCP binding at 4 degrees C; instead, it decreased binding at 21 degrees C. This inhibitory effect of A2C on TCP binding was dose dependent and was highly correlated with A2C-induced increases in membrane fluidity. The IC50 of A2C inhibition was 8.9 mM, with a pseudo-Hill coefficient of -0.24. Scatchard analysis demonstrated that this effect was the result of an increase in the apparent KD of [3H]TCP for the PCP receptor, with no effect on the Bmax. These results suggest that the function of the NMDA-PCP receptor complex is impaired by increases in membrane fluidity. These findings may be pharmacologically relevant in understanding the mechanism of action of such agents as general anesthetics and ethanol, which cause increases in plasma membrane fluidity.
J Mol Neurosci 1990
PMID:Effects of membrane fluidity on [3H]TCP binding to PCP receptors. 217 11

The phencyclidine (PCP) receptor is a site within the ion channel gated by the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. In the present study, kinetics of association and dissociation of the specific PCP receptor ligand [3H]MK-801 were determined in order to elucidate the mechanism of functioning of the NMDA receptor complex. Two distinct components of [3H]MK-801 association with apparent t1/2 values of approximately 10 min and 3 hr were resolved. Incubation with the NMDA receptor agonist L-glutamate increased the total steady state binding of [3H]MK-801 and increased the relative percentage of [3H]MK-801 binding that manifested fast rather than slow kinetics, without altering the observed rate constant of either the fast or slow component of association. The competitive NMDA receptor antagonist D(-)-2-amino-5-phosphonovaleric acid decreased total steady state binding of [3H]MK-801. These data support a model in which [3H]MK-801 can gain access to its binding site via two distinct paths, a fast hydrophilic path associated with a conformation of the NMDA receptor in which the channel is open and a slow hydrophobic path independent of the open channel. In the presence of L-glutamate, incubation with glycine increased the relative percentage of [3H]MK-801 binding that manifested fast rather than slow kinetics. The Hill coefficient for stimulation of specific [3H]MK-801 binding by L-glutamate was significantly greater than unity in either the absence or presence of glycine. Our data support a model of NMDA receptor functioning in which two molecules of agonist are required to convert the receptor complex to a conformation that is in equilibrium with the open conformation and in which glycine regulates the percentage of NMDA receptor complexes bound to two molecules of agonist that convert to the open configuration.
Mol Pharmacol 1989 Apr
PMID:Biexponential kinetics of [3H]MK-801 binding: evidence for access to closed and open N-methyl-D-aspartate receptor channels. 246 76

The N-methyl-D-aspartate receptor-gated ion channel (NMDA channel) is regulated by glycine. To examine the interaction of glycine and NMDA receptor ligands on NMDA channel function, we used a biochemical marker of channel opening, [3H]N-(1-[thienyl]cyclohexyl)piperidine (TCP). We quantified [3H]glycine,L-[3H]glutamate, and TCP binding in an identical membrane preparation. This allowed direct comparison of NMDA and glycine receptor occupancy and channel activation. Glycine increased the association and dissociation rates of NMDA-dependent TCP binding to hippocampal membranes, without altering the Kd or Bmax for TCP binding. Structurally similar amino acids mimicked the action of glycine, with D-isomers being more potent than L-isomers. The potency of glycine in regulating TCP binding matched that for displacing [3H]glycine. Glycine stimulation of TCP binding required the presence of NMDA agonists and was inhibited by the NMDA antagonist D-2-amino-5-phosphonovaleric acid. Glycine stimulation of NMDA-dependent TCP binding was not associated with an increase in agonist binding to the NMDA receptor. Likewise, NMDA stimulation of glycine-dependent TCP binding was not associated with an increase in the binding of glycine to the glycine receptor. These findings permit the following conclusions: 1) glycine stimulates TCP binding solely by increasing the access of TCP to its site in the NMDA channel; 2) TCP binding can be used to quantify glycine regulation of the NMDA channel; 3) a stereospecific glycine receptor, as part of the NMDA receptor-channel complex, regulates NMDA-evoked channel opening by a mechanism not involving increased agonist binding to the NMDA receptor. Thus, it appears that the mechanism of glycine and NMDA receptor regulation of the NMDA channel is analogous to that of a two-key lock; both receptors, by independent and mutually required mechanisms, alter channel conformation to allow ion passage.
Mol Pharmacol 1989 Aug
PMID:Glycine regulation of the N-methyl-D-aspartate receptor-gated ion channel in hippocampal membranes. 247 59

The effects of N-methyl-D-aspartate (NMDA) on muscarinic receptor-stimulated phosphoinositide (PI) hydrolysis in rat cortical slices were studied. NMDA inhibits carbachol-stimulated PI hydrolysis with an IC50 of 9.8 +/- 1.4 microM and a maximal inhibition of 70% at 100 microM. The inhibitory effect of NMDA is not due to increased metabolism of accumulated inositol phosphates. NMDA inhibition of carbachol-stimulated PI hydrolysis was significantly reduced in the absence of extracellular calcium. Although the inhibitory effect of NMDA is observed in the presence of 1.18 mM Mg2+, the concentration-response curve is slightly shifted to the left (5-fold) in the absence of extracellular Mg2+. Antagonists of NMDA-evoked excitations were effective inhibitors of the NMDA modulation of PI hydrolysis, including the competitive antagonist 2-amino-5-phosphonopentanoic acid and the noncompetitive antagonist MK-801. The rank order of potencies of the antagonists were MK-801 greater than phencyclidine = (-)-cyclazocine greater than ketamine = etoxadrol greater than N-allylnormetazocine greater than 2-amino-5-phosphonopentanoic acid. (+)-MK-801 and (-)-cyclazocine were more potent inhibitors, by 4-5-fold, of the NMDA response than their respective isomers, whereas N-allylnormetazocine isomers were approximately equipotent antagonists. The activity of dexoxadrol against NMDA inhibition of carbachol-stimulated PI hydrolysis could not be determined because of its antimuscarinic effects. The rank order of potencies of antagonists, the stereoselectivity of the isomers of MK-801, cyclazocine, and N-allylnormetazocine, and Mg2+ sensitivity of the NMDA inhibitory response suggest that a phencyclidine binding similar to the one located in the cation channel gated by NMDA receptors is associated with the NMDA receptor that modulates muscarinic-stimulated PI hydrolysis.
Mol Pharmacol 1989 Jun
PMID:A phencyclidine recognition site is associated with N-methyl-D-aspartate inhibition of carbachol-stimulated phosphoinositide hydrolysis in rat cortical slices. 254 12


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