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)

Epilepsy is closely related to an altered transmission of GABA, the major inhibitory transmitter in the brain. GABA acts through two classes of receptors, ionotropic GABA(A) receptors and metabotropic GABA(B) receptors. Using in situ hybridization, receptor autoradiography and immunocytochemistry, we now investigated temporal changes in the expression the GABA(B)-1 and GABA(B)-2 subunits (GABA(B)-1R and GABA(B)-1R, respectively) in the hippocampus following kainic-acid-induced seizures. Significant decreases (by about 40%) in mRNA levels of both splice variants (a and b) of GABA(B)-1R and of GABA(B)-2R were observed in the principal cell layer of the hippocampus 6-12 h after kainic acid injection in the rat. Whereas mRNA levels in the granule cell layer returned to basal after 24 h, the decreases persisted in sectors CA1 and CA3, presumably due to progressing neurodegeneration. In the sector CA3, GABA(B)-R mRNA levels and GABA(B)-R1 immunoreactivity partially recovered 30 days after the initial kainic acid seizures indicating receptor upregulation in surviving neurons.
Brain Res Mol Brain Res 2003 May 12
PMID:Altered expression of GABAB receptors in the hippocampus after kainic-acid-induced seizures in rats. 1275 12

The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of ionotropic glutamate receptors consists of rapidly gating ion channels. Positive modulation of channel gating may slow gating kinetics through at least two distinct mechanisms, evidenced by the predominant slowing of either the rate of receptor desensitization or the rate of offset after agonist withdrawal (deactivation). This study compares the actions of two positive allosteric modulators [cyclothiazide, which modulates desensitization, and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546), which modulates deactivation] in a mutant shown previously to impede modulation by cyclothiazide. These experiments test the hypothesis that the point mutation, GluR1(S493T), would also cause a loss of modulation by CX546. Wild-type GluR1 through -4 receptors were modulated by CX546, as assayed by the potentiation of steady-state currents in the Xenopus laevis oocyte expression system. CX546 potentiated steady-state currents of both splice isoforms of GluR1. Modulation by CX546 was completely abolished in GluR1(S493T) and its homolog, GluR2(S497T), although this mutation did not affect apparent agonist affinity in the absence of CX546. Thus, the GluR1(S493T) mutation has a similar impairment of modulation by either cyclothiazide or CX546, indicating that some residues at the subunit interface of glutamate receptors play an important role in channel deactivation and desensitization.
Mol Pharmacol 2003 Jul
PMID:Identification of a site in GluR1 and GluR2 that is important for modulation of deactivation and desensitization. 1281 55

We earlier showed that the ionotropic glutamate receptor agonist N-methyl D-aspartate (NMDA) induces excitotoxic pulmonary edema, and that endogenous activation of NMDA receptors (NMDAR) could mediate lung injury caused by oxidative stress. In this study, we searched for evidence of NMDAR expression in the rat lung and in the alveolar macrophage (AM) cell line NR8383, and for possible regulation of receptor expression by NMDA. The presence of mRNA for NMDAR 1 and the four known NMDAR 2 subtypes (A, B, C, and D) was examined by reverse transcriptase-polymerase chain reaction using isoform-specific primers. NMDAR 1 was expressed in all lung regions examined (peripheral, midlung, and mainstem), as well as in trachea and the AMs. Expression of NMDAR 2A and 2B subtypes was not detected, whereas NMDAR 2C was present only in peripheral and mid-lung samples. NMDAR 2D was the dominant subtype expressed in the peripheral, gas-exchange zone of lung and in alveolar macrophages, and this expression was upregulated in lungs treated with NMDA. Western blot confirmed the presence of NMDAR 1 protein in all lung regions and in AMs. These findings provide a molecular-biological basis for the excitotoxic actions of glutamate in rat lungs and airways, and raise the question of a possible physiologic role for NMDAR in lung and airway function.
Am J Respir Cell Mol Biol 2004 Feb
PMID:Ionotropic glutamate receptors in lungs and airways: molecular basis for glutamate toxicity. 1285 8

The molecular mechanisms that couple agonist binding to the gating of Cys-loop ionotropic receptors are not well understood. The crystal structure of the acetylcholine (ACh) binding protein has provided insights into the structure of the extracellular domain of nicotinic receptors and a framework for testing mechanisms of activation. Key ligand binding residues are located at the C-terminal end of the beta9 strand. At the N-terminal end of this strand (loop 9) is a conserved glutamate [E172 in chick alpha7 nicotinic acetylcholine receptors (nAChRs)] that is important for modulating activation. We hypothesize that agonist binding induces the movement of loop 9. To test this, we used the substituted-cysteine accessibility method to examine agonist-dependent changes in the modification of cysteines introduced in loop 9 of L247T alpha7 nAChRs. In the absence of agonist, ACh-evoked responses of E172C/L247T alpha7 nAChRs were inhibited by 2-trimethylammonioethylmethane thiosulfonate (MTSET). Agonist coapplication with MTSET reduced the extent and rate of modification. The dose-dependence of ACh activation was nearly identical with that of ACh-dependent protection from modification. ACh increased the inhibition by methanethiosulfonate reagents of N170C and did not change inhibition of G171C receptors. The antagonist dihydro-beta-erythroidine did not mimic the effects of ACh. Combined with a structural model, the data suggest that receptor activation includes subunit rotation and/or intrasubunit conformational changes that move N170 to a more accessible position and E172 to a more protected position away from the vestibule. Thus, loop 9, located near the junction between the extracellular and transmembrane domains, participates in conformational changes triggered by ligand binding.
Mol Pharmacol 2003 Sep
PMID:Agonist-induced conformational changes in the extracellular domain of alpha 7 nicotinic acetylcholine receptors. 1292 Feb 1

Glutamate mediates its effects in mammals through both ionotropic and metabotropic receptors. Antagonists of ionotropic N-methyl-D-aspartate (NMDA) glutamate receptors elicit neuroprotective and neurotropic effects that have been attributed to Ca2+ block through the membrane ion channel. Nonetheless, molecular and biochemical effects of NMDA receptor antagonism on other glutamate receptor subunits remain poorly understood. We investigated the effects of acute administration of the noncompetitive NMDA receptor antagonist MK-801 on the mRNA expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and metabotropic glutamate receptor (mGluR) subunits to determine the contribution of different glutamate receptors in response to blockade of NMDA receptor channels. In situ hybridization to rat brain sections revealed that AMPAreceptor subunits GluR3 and GluR4, and mGluR3 were modestly but significantly decreased approximately 10-20%, 8 h following 5 mg/kg MK-801 administration. Atime course and dose response study revealed that the effect on mGluR3 was reversed by 24 h and occurred significantly at a dose range from 1 to 5 mg/kg. These results indicate that selected AMPA and mGluR subunit mRNAs respond at the RNA level to the blockade of NMDA receptors.
J Mol Neurosci 2003
PMID:Subunit selective decrease of AMPA and metabotropic glutamate receptor mRNA expression in rat brain by systemic administration of the NMDA receptor blocker MK-801. 1450 Sep 91

The activity of the N-methyl-D-aspartate (NMDA) receptor, a subclass of ionotropic glutamate receptor, is modulated by a complex network of phosphorylation and dephosphorylation. I investigated the relative extent of tyrosine phosphorylation of NMDA receptor subunit 2A (NR2A) and 2B (NR2B) subunits in the rat forebrain postsynaptic density (PSD) fraction. Immunoblot analysis of immunoprecipitates with antiphosphotyrosine antibodies indicated that tyrosine phosphorylation of NR2A was only 28.6% of that of NR2B. When phosphotyrosine-containing peptides were isolated by affinity-purification or immunoprecipitation, and probed for the two subunits, NR2B was detected but not NR2A. Furthermore, depletion of NR2B removed the phosphotyrosine-containing 180 kDa peptide from the solution while the converse was not true. The small extent of tyrosine phosphorylation of NR2A in the unstimulated condition may explain the dramatic increase in tyrosine phosphorylation in various physiological and pathological conditions.
Mol Cells 2003 Aug 31
PMID:Relative extent of tyrosine phosphorylation of the NR2A and NR2B subunits in the rat forebrain postsynaptic density fraction. 1450 41

The effects of gamma-amino butyric acid (GABA) and glutamate, their ionotropic agonists and antagonists on hydra's ectodermal and endodermal pacemaker systems were studied. GABA decreased ectodermal body contraction bursts (CBs) and the number of pulses in a burst (P/CB) and endodermal rhythmic potentials (RPs); tentacle pulses (TPs) were not affected. The GABA(A) agonist, muscimol, and the benzodiazepine receptor agonist, diazepam, mimicked the effects of GABA on the endodermal system. The GABA(A) antagonist bicuculline counteracted GABA's effects. Low concentrations of glutamate increased CBs and RPs. Higher concentrations required concanavalin A (Con A) to produce the same effect on CBs and P/CB. TPs were increased by high concentrations of glutamate and kainate. The ionotropic glutamate agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) also required Con A to increase CBs and RPs. The effects of AMPA were antagonized by 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione (NBQX), which, per se, decreased CBs. The results indicate that GABA and glutamate, acting on their ionotropic receptors, modify the impulses of hydra's pacemaker systems. On the whole GABA decreased the outputs of both ectodermal and endodermal impulse generating systems, while glutamate increased them.
Comp Biochem Physiol A Mol Integr Physiol 2003 Oct
PMID:GABA and glutamate receptors are involved in modulating pacemaker activity in hydra. 1451 52

Two glutamate receptor agonists, NMDA (N-methyl-D-aspartic acid) and ACPD (cis-(1S/3R)-1-aminocyclopentane- 1,3-dicarboxylic acid), induce the reactive oxygen species (ROS) production in rat cerebellum granule cells, whereas the third one, 3-HPG (3-hydroxyphenylglycine), decreases this parameter. The simultaneous presence of 3-HPG, together with NMDA or ACPD, prevents the generation of ROS by neuronal cells. A similar effect of these ligands on Na+/K+-ATPase can be demonstrated: NMDA and ACPD inhibited the enzyme activity, but 3-HPG activated Na+/K+-ATPase and prevented its inhibition by NMDA or ACPD. In terms of current classification, NMDA is an agonist of ionotropic glutamate receptors of the so-called NMDA class, whereas ACPD and 3-HPG belong to metabotropic agonists, the former primarily being an activator of metabotropic glutamate receptors (mGluRs) of groups 2 and 3, and the latter, that of mGluRs of groups 1 and 5. Thus, the data presented illustrate the existence of diverse mechanisms of the cross talk between Na+/K+-ATPase and different glutamate receptors, as well as that between glutamate receptors of different classes.
J Mol Neurosci 2003
PMID:Glutamate receptors communicate with Na+/K+-ATPase in rat cerebellum granule cells: demonstration of differences in the action of several metabotropic and ionotropic glutamate agonists on intracellular reactive oxygen species and the sodium pump. 1464 88

Multiple neurotransmitter systems have been implicated in the pathophysiology of schizophrenia. Dopamine hyperactivity has often been implicated in this illness. More recently, the glutamate hypothesis of schizophrenia suggests that NMDA receptor (NMDAR) hypofunction may also play a role in this illness. This is based primarily on studies showing that phencyclidine, an NMDAR antagonist, can induce a schizophreniform psychosis. While NMDAR dysfunction is most often implicated in schizophrenia, other components of the glutamate system, such as the AMPA and kainate receptors, as well as NMDAR-associated intracellular proteins, may also play a role in regulating NMDA receptor activity and glutamate neurotransmission. There is growing interest in the hypothesis that the pathophysiology of schizophrenia involves alterations in dopamine-glutamate interactions. The glutamate system is anatomically and functionally linked to the dopamine system, and glutamate can modulate dopaminergic activity and release by stimulating various glutamate receptor subtypes expressed by dopaminergic neurons in the substantia nigra/ventral tegmental area. In this study, we investigated dopamine-glutamate interactions by measuring the expression of transcripts encoding the subunits for the ionotropic glutamate receptors (NMDA, AMPA and kainate) and five NMDAR-associated intracellular proteins, PSD-93, PSD-95, SAP102, NF-L and yotiao in the dopaminergic neurons in the substantia nigra pars compacta (SNc) of subjects with schizophrenia and a comparison group. Tyrosine hydroxylase (TH, a marker of dopamine-synthesizing cells), NR1 (an NMDA receptor subunit) and GluR5 (a kainate subunit) transcript levels were significantly increased in the SNc in schizophrenia. These data support the hypothesis that schizophrenia may involve alterations in dopamine-glutamate interactions.
Brain Res Mol Brain Res 2004 Feb 05
PMID:Expression of the ionotropic glutamate receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in schizophrenia. 1496 37

The central role of glutamate receptors in mediating excitotoxic neuronal death in stroke, epilepsy and trauma has been well established. Glutamate is the major excitatory amino acid transmitter within the CNS and it's signaling is mediated by a number of postsynaptic ionotropic and metabotropic receptors. Although calcium ions are considered key regulators of excitotoxicity, new evidence suggests that specific second messenger pathways rather than total Ca(2+) load, are responsible for mediating neuronal degeneration. Glutamate receptors are found localized at the synapse within electron dense structures known as the postsynaptic density (PSD). Localization at the PSD is mediated by binding of glutamate receptors to submembrane proteins such as actin and PDZ containing proteins. PDZ domains are conserved motifs that mediate protein-protein interactions and self-association. In addition to glutamate receptors PDZ-containing proteins bind a multitude of intracellular signal molecules including nitric oxide synthase. In this way PDZ proteins provide a mechanism for clustering glutamate receptors at the synapse together with their corresponding signal transduction proteins. PSD organization may thus facilitate the individual neurotoxic signal mechanisms downstream of receptors during glutamate overactivity. Evidence exists showing that inhibiting signals downstream of glutamate receptors, such as nitric oxide and PARP-1 can reduce excitotoxic insult. Furthermore we have shown that uncoupling the interaction between specific glutamate receptors from their PDZ proteins protects neurons against glutamate-mediated excitotoxicity. These findings have significant implications for the treatment of neurodegenerative diseases using therapeutics that specifically target intracellular protein-protein interactions.
Curr Mol Med 2004 Mar
PMID:Molecular mechanisms underlying specificity of excitotoxic signaling in neurons. 1503 10


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