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Gene Review

Grm4  -  glutamate receptor, metabotropic 4

Rattus norvegicus

Synonyms: Gprc1d, Metabotropic glutamate receptor 4, Mglur4, mGluR4
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Disease relevance of Grm4

  • In the ganglion cell layer, virtually every ganglion cell and displaced amacrine cell was labelled for mGluR1 and mGluR4 [1].
  • Changes in metabotropic glutamate receptor mRNA levels following global ischemia: increase of a putative presynaptic subtype (mGluR4) in highly vulnerable rat brain areas [2].
  • We conclude that activation of the mGluR4 receptor protects hippocampal neurons from NO toxicity and that the mechanism of NO induced neurodegeneration does not appear to involve inhibition of the mGluR1 receptor subtype activity or the phosphoinositide system [3].
  • Group II (mGluR2 and 3) and group III mGluR (mGluR4, 6, 7, 8) are novel targets for inhibition of vagal signaling with therapeutic potential in, for example, GERD [4].
  • When medium-sized spiny neurons (MSNs) were labeled with Sindbis virus expressing membrane-targeted green fluorescent protein, mGluR4 immunoreactivity was observed on some varicosities of their axon collaterals in immunofluorescence and immunoelectron microscopies [5].

High impact information on Grm4

  • We previously identified the metabotropic glutamate receptor 4 (mGluR4) as a potential drug target and predicted that selective activation of mGluR4 could provide palliative benefit in PD [6].
  • This compound selectively potentiated agonist-induced mGluR4 activity in cultured cells expressing this receptor and did not itself act as an agonist [6].
  • The closely related analogue 7-(hydroxylimino)cyclopropachromen-1a-carboxamide ethyl ester, which does not potentiate mGluR4, had no effect in this model [6].
  • Upregulation of presynaptic mGluR4 in pup CA3 neurons could lead to reduced transmitter release from CA3 axons, including recurrent collaterals, thereby reducing vulnerability of neonatal CA3 neurons to seizure-induced damage [7].
  • These data are consistent with a largely presynaptic role of mGluR7 in the hippocampus and suggest that mGluR4 may have both presynaptic and postsynaptic functions [8].

Biological context of Grm4


Anatomical context of Grm4


Associations of Grm4 with chemical compounds

  • These data are consistent with the possibility that in primary cultures of cerebellar neurons, phosphoinositide responses may be predominantly mediated by mGluR1a, rather than mGluR5, and that cAMP inhibition involves preferentially mGluR4 and mGluR3 [14].
  • Three groups of mGluRs have been described: group 1 (mGluR1 and 5) receptors are positively coupled to phospholipase C whereas group 2 (mGluR2 and 3) and group 3 (mGluR4, 6, 7 and 8) receptors are negatively coupled to adenylate cyclase [15].
  • Activation of group I receptors (mGluR1 and/or mGluR5) on presynaptic somata/dendrites led to an increase in spike-dependent transmitter release, whereas activation of the group III receptors (mGluR4, 7, and/or 8) on presynaptic terminals suppressed glutamate and GABA release onto SON neurons [16].
  • [(3)H]L-AP4 binding to mGluR4 required chloride ions but not monovalent or divalent cations [17].
  • In parallel experiments, no activities of these phenylglycine analogs at mGluR4 were observed [18].

Other interactions of Grm4

  • Consistent with previous studies, one receptor subtype is an L-AP4-sensitive receptor that is pharmacologically similar to mGluR4 or mGluR7 [19].
  • Intrathecal (i.t.) administration of the mGluR4/mGluR6-mGluR8 agonist, L(+)-2-amino-4-phosphonobutyric acid (L-AP4), the mGluR1/mGluR5 antagonists [20].
  • Both mGluR3 and mGluR4 inhibit the forskolin-stimulated accumulation of intracellular cAMP formation in response to agonist interaction [9].
  • Maintaining the granule neurons in vitro in 10 mM KCl increased the absolute amount of mRNAs encoding mGluR2 and mGluR4 at 9 and 13 days in vitro [14].
  • RT-PCR and immunological analyses indicated that mGluR4, a class III mGluR, was expressed and localized with alpha- and F cells, whereas no evidence for expression of other mGluRs, including mGluR8, was obtained [21].

Analytical, diagnostic and therapeutic context of Grm4


  1. Expression of the mRNA of seven metabotropic glutamate receptors (mGluR1 to 7) in the rat retina. An in situ hybridization study on tissue sections and isolated cells. Hartveit, E., Brandstätter, J.H., Enz, R., Wässle, H. Eur. J. Neurosci. (1995) [Pubmed]
  2. Changes in metabotropic glutamate receptor mRNA levels following global ischemia: increase of a putative presynaptic subtype (mGluR4) in highly vulnerable rat brain areas. Iversen, L., Mulvihill, E., Haldeman, B., Diemer, N.H., Kaiser, F., Sheardown, M., Kristensen, P. J. Neurochem. (1994) [Pubmed]
  3. Activation of the metabotropic glutamate receptor is neuroprotective during nitric oxide toxicity in primary hippocampal neurons of rats. Maiese, K., Greenberg, R., Boccone, L., Swiriduk, M. Neurosci. Lett. (1995) [Pubmed]
  4. Metabotropic glutamate receptors inhibit mechanosensitivity in vagal sensory neurons. Page, A.J., Young, R.L., Martin, C.M., Umaerus, M., O'Donnell, T.A., Cooper, N.J., Coldwell, J.R., Hulander, M., Mattsson, J.P., Lehmann, A., Blackshaw, L.A. Gastroenterology (2005) [Pubmed]
  5. Metabotropic glutamate receptor 4-immunopositive terminals of medium-sized spiny neurons selectively form synapses with cholinergic interneurons in the rat neostriatum. Kuramoto, E., Fujiyama, F., Unzai, T., Nakamura, K., Hioki, H., Furuta, T., Shigemoto, R., Ferraguti, F., Kaneko, T. J. Comp. Neurol. (2007) [Pubmed]
  6. Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment. Marino, M.J., Williams, D.L., O'Brien, J.A., Valenti, O., McDonald, T.P., Clements, M.K., Wang, R., DiLella, A.G., Hess, J.F., Kinney, G.G., Conn, P.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. Status epilepticus-induced alterations in metabotropic glutamate receptor expression in young and adult rats. Aronica, E.M., Gorter, J.A., Paupard, M.C., Grooms, S.Y., Bennett, M.V., Zukin, R.S. J. Neurosci. (1997) [Pubmed]
  8. Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies. Bradley, S.R., Levey, A.I., Hersch, S.M., Conn, P.J. J. Neurosci. (1996) [Pubmed]
  9. Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4. Tanabe, Y., Nomura, A., Masu, M., Shigemoto, R., Mizuno, N., Nakanishi, S. J. Neurosci. (1993) [Pubmed]
  10. Decreased expression of the metabotropic glutamate receptor-4 gene is associated with neuronal apoptosis. Borodezt, K., D'Mello, S.R. J. Neurosci. Res. (1998) [Pubmed]
  11. Control of Ca(2+) influx by cannabinoid and metabotropic glutamate receptors in rat cerebellar cortex requires K(+) channels. Daniel, H., Crepel, F. J. Physiol. (Lond.) (2001) [Pubmed]
  12. Differential distribution of metabotropic glutamate receptor subtype mRNAs in the thalamus of the rat. Lourenço Neto, F., Schadrack, J., Berthele, A., Zieglgänsberger, W., Tölle, T.R., Castro-Lopes, J.M. Brain Res. (2000) [Pubmed]
  13. Distribution of metabotropic glutamate receptors in the superior colliculus of the adult rat, ferret and cat. Cirone, J., Sharp, C., Jeffery, G., Salt, T.E. Neuroscience (2002) [Pubmed]
  14. Temporal and depolarization-induced changes in the absolute amounts of mRNAs encoding metabotropic glutamate receptors in cerebellar granule neurons in vitro. Santi, M.R., Ikonomovic, S., Wroblewski, J.T., Grayson, D.R. J. Neurochem. (1994) [Pubmed]
  15. Metabotropic glutamate receptors inhibiting excitatory synapses in the CA1 area of rat hippocampus. Manzoni, O., Bockaert, J. Eur. J. Neurosci. (1995) [Pubmed]
  16. Presynaptic modulation by metabotropic glutamate receptors of excitatory and inhibitory synaptic inputs to hypothalamic magnocellular neurons. Schrader, L.A., Tasker, J.G. J. Neurophysiol. (1997) [Pubmed]
  17. Ion dependence of ligand binding to metabotropic glutamate receptors. Kuang, D., Hampson, D.R. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  18. Actions of phenylglycine analogs at subtypes of the metabotropic glutamate receptor family. Thomsen, C., Boel, E., Suzdak, P.D. Eur. J. Pharmacol. (1994) [Pubmed]
  19. Multiple presynaptic metabotropic glutamate receptors modulate excitatory and inhibitory synaptic transmission in hippocampal area CA1. Gereau, R.W., Conn, P.J. J. Neurosci. (1995) [Pubmed]
  20. The contribution of metabotropic glutamate receptors (mGluRs) to formalin-induced nociception. Fisher, K., Coderre, T.J. Pain (1996) [Pubmed]
  21. Metabotropic glutamate receptor type 4 is involved in autoinhibitory cascade for glucagon secretion by alpha-cells of islet of Langerhans. Uehara, S., Muroyama, A., Echigo, N., Morimoto, R., Otsuka, M., Yatsushiro, S., Moriyama, Y. Diabetes (2004) [Pubmed]
  22. Changes in mRNA for metabotropic glutamate receptors after transient cerebral ischaemia. Rosdahl, D., Seitzberg, D.A., Christensen, T., Balchen, T., Diemer, N.H. Neuroreport (1994) [Pubmed]
  23. Cyclosporine-A treatment inhibits the expression of metabotropic glutamate receptors in rat thymus. Rezzani, R., Corsetti, G., Rodella, L., Angoscini, P., Lonati, C., Bianchi, R. Acta Histochem. (2003) [Pubmed]
  24. Subtype-specific expression of group III metabotropic glutamate receptors and Ca2+ channels in single nerve terminals. Millán, C., Luján, R., Shigemoto, R., Sánchez-Prieto, J. J. Biol. Chem. (2002) [Pubmed]
  25. Distributions of the mRNAs for L-2-amino-4-phosphonobutyrate-sensitive metabotropic glutamate receptors, mGluR4 and mGluR7, in the rat brain. Ohishi, H., Akazawa, C., Shigemoto, R., Nakanishi, S., Mizuno, N. J. Comp. Neurol. (1995) [Pubmed]
  26. A subtype of the metabotropic glutamate receptor family in the olfactory system of Atlantic salmon. Pang, J., Lo, Y.H., Chandlee, J.M., Rhoads, D.E. FEBS Lett. (1994) [Pubmed]
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