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)

Within the hippocampus, electrophysiological and immunohistochemical studies showed that metabotropic glutamate receptor subtype 5 (mGluR5) is the major postsynaptic mGluR expressed in CA1 pyramidal neurons. To better understand the role of mGluR5 in ischemia-induced neuronal death, whole-cell patch-clamp recordings using hippocampal slices were performed to investigate the functional change of mGluR5 in CA1 pyramidal neurons following transient global ischemia. Our results indicated that 6 to 24 h after global ischemia, mGluR5-induced cationic currents and mGluR5-mediated enhancement of NMDA-evoked currents in CA1 pyramidal neurons were significantly reduced. Further TaqMan real-time quantitative RT-PCR assay showed that mGluR5 mRNA expression in hippocampal CA1 region or single CA1 pyramidal neurons was significantly downregulated following ischemic insults. The present study suggests that transient global ischemia downregulates mGluR5 function of CA1 pyramidal neurons by decreasing mGluR5 mRNA and that the resulting reduced mGluR5-mediated excitotoxicity could contribute to the survival of CA1 pyramidal neurons after ischemic insult.
Mol Cell Neurosci 2005 Jul
PMID:Global ischemia downregulates the function of metabotropic glutamate receptor subtype 5 in hippocampal CA1 pyramidal neurons. 1588 47

Recent studies suggest that glutamate plays a pivotal role in the processing of sensory information in the spinal cords of patients with diabetic neuropathy. However, the specific glutamate receptors that that are involved have yet to be determined. We therefore conducted a study to characterize the expression of messenger RNAs (mRNAs) coding for subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and N-methyl-d-aspartate (NMDA) receptors and for metabotropic glutamate receptors (mGluRs) in the dorsal horn of the lumbar segment of the spinal cord in a rat model (streptozotocin [STZ]-induced) of diabetic neuropathy. The levels of mRNAs coding for AMPA receptor subunits, GluR1, GluR2, and GluR3, were significantly increased in all layers (laminae I-V) of the dorsal horn in diabetic (STZ-injected) rats compared to control (vehicle-injected) rats. The hybridization signals for NR2A mRNA and NR2B mRNA were significantly elevated in the deep layer of the dorsal horn of diabetic rats. In diabetic (STZ-induced) rats, the levels of expression of mGluR1 mRNA and mGluR5 mRNA were significantly increased in all layers of the dorsal horn. These results suggest that abnormal expression of multiple glutamate receptors is involved in the development of diabetic neuropathy and that glutamate receptors are promising targets in the treatment of this disorder.
Brain Res Mol Brain Res 2005 May 20
PMID:Upregulation of mRNAs coding for AMPA and NMDA receptor subunits and metabotropic glutamate receptors in the dorsal horn of the spinal cord in a rat model of diabetes mellitus. 1589 11

Prepulse inhibition (PPI) is a cross-species measure of sensorimotor gating. PPI deficits have been associated with a number of neuropsychiatric disorders, including schizophrenia. Differential PPI has been demonstrated also across various inbred mouse strains; however, the molecular mechanisms underlying these differences in sensorimotor gating remain unclear. Here, we sought to identify gene expression in the medial prefrontal cortex (mPFC) of mice associated with PPI using a laser microdissection and microarray analysis-based approach. C57BL/6 mouse substrains were used for the study as they have dramatically different PPI. Transcriptional analysis of closely related substrains was predicted to reduce the detection of genetic variation incidental to the phenotype. Microarray analysis comparing the mPFC of C57BL/6J to C57BL/6NHsd mice revealed neurotransmission- and cellular stress-related transcriptional responses associated with lower PPI. Down-regulation of metabotropic glutamate receptor 5, phospholipase C, and inositol monophosphatase 1 gene expression suggest altered phosphoinositide signaling, while decreased expression of a gamma-amino-butyric acid (GABA)A receptor subunit implies changes in GABAergic signaling. Genes involved in neuronal excitation and protection were also differentially expressed, including up-regulation of five immediate early genes and anti-apoptotic/survival factors as Bcl2-associated athanogene 3 and brain-derived neurotrophic factor. These data support previous findings of genetic influences on PPI, and provide novel insights into the molecular mechanisms regulating sensorimotor gating.
Brain Res Mol Brain Res 2005 Sep 13
PMID:Neurotransmission- and cellular stress-related gene expression associated with prepulse inhibition in mice. 1596 Nov 83

Complementation of function after coexpression of pairs of nonfunctional G protein-coupled receptors that contain distinct inactivating mutations supports the hypothesis that such receptors exist as dimers. Chimeras between members of the metabotropic glutamate receptor-like family have been particularly useful because the N-terminal ligand binding and heptahelical transmembrane elements can be considered distinct domains. To examine the utility of a related approach for opioid receptors, fusion proteins were generated in which a pertussis toxin-resistant (Cys351Ile) variant of the G protein Gi1alpha was linked to the C-terminal tails of the delta opioid peptide (DOP), kappa opioid peptide, and mu opioid peptide receptors. Each was functional as measured by agonist stimulation of guanosine 5'-([gamma-35S]thio)triphosphate ([35S]GTPgammaS) binding in Gialpha immunoprecipitates from membranes of pertussis toxin-treated HEK293 cells. Agonist function was eliminated either by fusion of the receptors to Gi1alphaGly202Ala,Cys351Ile or mutation of a pair of conserved Val residues in intracellular loop 2 of each receptor. Coexpression, but not simple mixing, of the two inactive fusion proteins reconstituted agonist-loading of [35S]GTPgammaS for each receptor. At equimolar amounts, reconstitution of DOP receptor function was more extensive than kappa or mu opioid receptor. Reconstitution of DOP function required two intact receptors and was not achieved by provision of extra Gi1alphaCys351Ile membrane anchored by linkage to DOP transmembrane domain 1. Inactive forms of all G protein alpha subunits can be produced by mutations equivalent to Gi1alphaGly202Ala. Because the amino acids modified in the opioid receptors are highly conserved in most rhodopsin-like receptors, this approach should be widely applicable to study the existence and molecular basis of receptor dimerization.
Mol Pharmacol 2005 Sep
PMID:Functional complementation and the analysis of opioid receptor homodimerization. 1596 73

The metabotropic glutamate receptor subtype 5 (mGlu5) activates calcium mobilization via binding of glutamate, the major excitatory neurotransmitter in the central nervous system. Allosteric modulation of the receptor has recently emerged as a promising alternative method of regulation to traditional regulation through orthosteric ligands. We now report three novel compounds that bind to the allosteric 2-methyl-6-(phenylethynyl)-pyridine (MPEP) site on mGlu5 but have only partial inhibition or no functional effects on the mGlu5 response. Two of these compounds, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP) and 2-(2-(5-bromopyridin-3-yl)ethynyl)-5-methylpyridine (Br-5MPEPy), act as partial antagonists of mGlu5 in that they only partially inhibit the response of this receptor to glutamate. The third compound, 5-methyl-6-(phenylethynyl)-pyridine (5MPEP), acts as a neutral allosteric site ligand that binds to the MPEP site and has no effects alone. However, 5MPEP blocks the effects of both the allosteric antagonist MPEP and potentiators 3,3'-difluorobenzaldazine and 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB). This compound also blocks depolarization effects of both MPEP and CDPPB in neurons in the subthalamic nucleus. These novel compounds provide valuable new insight into the pharmacology of allosteric sites on G protein-coupled receptors and provide valuable new tools for determining the effects of allosteric site ligands in native systems.
Mol Pharmacol 2005 Dec
PMID:A close structural analog of 2-methyl-6-(phenylethynyl)-pyridine acts as a neutral allosteric site ligand on metabotropic glutamate receptor subtype 5 and blocks the effects of multiple allosteric modulators. 1615 10

The extracellular calcium sensing receptor (CaSR) belongs to the type III family of G-protein-coupled receptors, a family that comprises the metabotropic glutamate receptor and the putative vomeronasal organ receptors. The CaSR plays an important role for calcium homeostasis in parathyroid cells, kidney cells and other cells to directly 'sense' changes in the extracellular calcium ion concentration ([Ca2+]o). The mesangial cells are known to be involved in many pathologic sequences through the mediation of altered glomerular hemodynamics, cell proliferation, and matrix production. In this study, we examined the expression of the CaSR in the mouse mesangial cell lines (MMC, ATCC number CRL-1927). Reverse transcription-polymerase chain reaction (RT-PCR) was perform with CaSR-specific primers, and this was followed by nucleotide sequencing of the amplified product; this process identified the CaSR transcript in the MMCs. Moreover, CaSR protein was present in the MMCs as assessed by Western blot and immunocytochemical analysis using a polyclonal antibody specific for the CaSR. Functionally, [Ca2+]o induced the increment of the intracellular calcium concentration ([Ca2+]i) in a dose-dependent manner. This [Ca2+]i increment by [Ca2+]o was attenuated by the pretreatment with a phospholipase C inhibitor (U73122) and also by a pretreatment with a CaSR antagonist (NPS 2390). The similar results were also obtained in IP3 accumulation by [Ca2+]o. To investigate the physiological effect of the CaSR, the effect of the [Ca2+]o on cell proliferation was studied. The increased [Ca2+]o (up to 10 mM) produced a significant increase in the cell numbers. This mitogenic effect of [Ca2+]o was inhibited by the co-treatment with a CaSR antagonist. From these results, the [Ca2+]o-induced [Ca2+]i elevation in the MMC is coupled with the extracellular calcium sensing receptor. Furthermore, [Ca2+]o produces a mitogenic effect in MMCs.
Exp Mol Med 2005 Oct 31
PMID:The extracellular calcium sensing receptor is expressed in mouse mesangial cells and modulates cell proliferation. 1626 70

Many membrane proteins incur a folding problem during biosynthesis; only a fraction thereof is exported from the endoplasmic reticulum (ER), because quality control is stringent. This is also true for G protein-coupled receptors. Here, we identify the deubiquitinating enzyme Usp4 as an interaction partner of the A2a adenosine receptor, a Gs-coupled receptor. Usp4 binds to the carboxyl terminus of the A2A receptor and allows for its accumulation as deubiquinated protein. This relaxes ER quality control and enhances cell surface expression of functionally active receptor. The effect of Usp4 on the A2A receptor was specific because 1) it was not seen in C-terminally truncated versions of the receptor; 2) it was not mimicked by Usp14, another member of the ubiquitin-specific protease family; and 3) it was not seen with the metabotropic glutamate receptor-5, another G protein-coupled receptor with a high propensity for intracellular retention. These observations show that deubiquinating enzymes can regulate quality control in the ER.
Mol Pharmacol 2006 Apr
PMID:The ubiquitin-specific protease Usp4 regulates the cell surface level of the A2A receptor. 1642 Dec 89

Understanding the molecular bases of sweet taste is of crucial importance not only in biotechnology but also for its medical implications, since an increasing number of people is affected by food-related diseases like, diabetes, hyperlipemia, caries, that are more or less directly linked to the secondary effects of sugar intake. Despite the interest paid to the field, it is only through the recent identification and functional expression of the receptor for sweet taste that new perspectives have been opened, drastically changing our approach to the development of new sweeteners. We shall give an overview of the field starting from the early days up to discussing the newest developments. After a review of early models of the active site, the mechanisms of interaction of small and macromolecular sweet molecules will be examined in the light of accurate modeling of the sweet taste receptor. The analysis of the homology models of all possible dimers allowed by combinations of the human T1R2 and T1R3 sequences of the sweet receptor and the closed (A) and open (B) conformations of the mGluR1 glutamate receptor shows that only 'type B' sites, either T1R2(B) and T1R3(B), can host the majority of small molecular weight sweeteners. Simultaneous binding to the A and B sites is not possible with two large sweeteners but is possible with a small molecule in site A and a large one in site B. This observation accounted for the first time for the peculiar phenomenon of synergy between some sweeteners. In addition to these two sites, the models showed an external binding site that can host sweet proteins.
J Mol Recognit
PMID:The history of sweet taste: not exactly a piece of cake. 1660 91

We recently reported a novel class of compounds, represented by 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CD-PPB), that act as positive allosteric modulators (potentiators) of metabotropic glutamate receptor (mGluR) subtype 5. Studies of CDPPB analogs revealed that some compounds in this series serve also as positive allosteric modulators of mGluR1. Although CDPPB is selective for mGluR5 relative to other mGluR subtypes, several CDPPB analogs also showed 2.5-fold potentiation of glutamate-induced calcium transients in cells expressing mGluR1 at 10 muM, with 4-nitro-N-(1,4-diphenyl-1H-pyrazol-5-yl)benzamide (VU-71) being selective for mGluR1. In previous studies, we found that two structural classes of mGluR5-selective allosteric potentiators, including CDPPB, share a common binding site with the allosteric mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine. Negative allosteric modulators of mGluR1, regardless of structural class, have been reported to bind to a common allosteric antagonist site on this receptor. However, neither the novel CDPPB analogs nor previously identified allosteric mGluR1 potentiators [e.g., (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476), ethyl diphenylacetylcarbamate (Ro 01-6128), and butyl (9H-xanthene-9-carbonyl)carbamate (Ro 67-4853)] displaced the binding of [(3)H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone (R214127), a high-affinity radioligand for the allosteric antagonist site on mGluR1 at concentrations several orders of magnitude higher than those required to induce allosteric potentiation of mGluR1 responses. These data suggest that allosteric potentiators of mGluR1 act at a site that is distinct from that of allosteric antagonists of mGluR1. Site-directed mutagenesis revealed that valine at position 757 in transmembrane V of mGluR1a is crucial for the activity of multiple classes of allosteric mGluR1 potentiators.
Mol Pharmacol 2006 Aug
PMID:A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators. 1664 24

The propagation of Ca2+ waves in a network of microglial cells, after its initiation by glutamate, is mediated by purinergic transmission. In this study, we investigated the mechanisms by which glutamate releases ATP from cultured spinal cord microglia. The 4-fold increase in ATP release from microglia in response to glutamate (0.5 mM) was blocked by alpha-aminohydroxy-5-methyl-isoxazole-4-proprionate (AMPA)/kainate receptor antagonist 6-cyano-7-nitroguinoxaline-2,3-dione and specific AMPA receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) but not by N-methyl-d-aspartic acid or metabotropic glutamate receptor antagonists. Glutamate acting on AMPA receptors evoked an ATP release that was blocked by antagonizing the rise in intracellular Ca2+ as a result of its release from internal stores as well as by antagonizing protein kinase C with chelerythrine. Glutamate-stimulated ATP release was significantly antagonized by the cystic fibrosis transmembrane conductance regulator (CFTR) blockers flufenamic acid and glibenclamide. A role for the CFTR was further confirmed using microglia from CFTR knockout mice, which released significantly less ATP than microglia from control wild-type mice in response to glutamate. Use of 6-methoxy-1-(3-sulfopropyl)quinolinium fluorescence assay revealed functional CFTR in microglia. These observations suggest that glutamate acted on microglial AMPA receptors to stimulate release of Ca2+ from intracellular stores as well as a Ca2+-dependent isoform of protein kinase C, which then acts to trigger release of ATP with the CFTR acting as a regulator of the ATP release process, perhaps through another channel or transporter.
Mol Pharmacol 2006 Sep
PMID:Purine release from spinal cord microglia after elevation of calcium by glutamate. 1676 Mar 62


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