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Gene Review

GRM2  -  glutamate receptor, metabotropic 2

Homo sapiens

Synonyms: GLUR2, GPRC1B, MGLUR2, Metabotropic glutamate receptor 2, mGlu2, ...
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Disease relevance of GRM2


Psychiatry related information on GRM2


High impact information on GRM2

  • Postsynaptic mGluR2 was activated by glutamate from granule cells and hyperpolarized Golgi cells via G protein-coupled inwardly rectifying K+ channels (GIRKs) [10].
  • Postsynaptic mGluR2 thus senses inputs from granule cells and is most likely important for spatiotemporal modulation of mossy fiber-granule cell transmission before distributing inputs to Purkinje cells [10].
  • Group I mGluRs (mGluR1 and 5) have excitatory effects on neurons, whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) are inhibitory [11].
  • The fact that constitutively active Galpha(i2) occludes the transient suppression of synaptic transmission by mGluR2, while enhancing LTD, suggests further that these two forms of plasticity are expressed via different mechanisms [12].
  • Here we show that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) at Schaffer collateral to CA1 synapses in postischemic hippocampus exhibit properties of Ca(2+)/Zn(2+)-permeable, Glu receptor 2 (GluR2)-lacking AMPARs before the rise in Zn(2+) and cell death [13].

Chemical compound and disease context of GRM2


Biological context of GRM2


Anatomical context of GRM2

  • [3H]-LY341495 bound to membranes expressing human mGlu2 and mGlu3 receptors in a reversible and saturable manner with relatively high affinities (Bmax 20.5 +/- 5.4 and 32.0 +/- 7.0 pmol/mg protein; and K(D) = 1.67 +/- 0.20 and 0.75 +/- 0.43 nM, respectively) [18].
  • Accordingly, DTT did not affect the inhibition of forskolin-stimulated cAMP formation induced by maximally effective concentrations of group-II mGlu receptor agonists in hippocampal slices or in CHO cells expressing mGlu2 receptors [19].
  • The results indicate that [(3)H]-1 should be a useful ligand for the study of mGluR2, 3, and 8 receptors in cloned cell lines and possibly brain tissue [20].
  • The mRNAs for mGluR1, 4 and 5 were observed in the spinal gray matter, whereas mGluR2 mRNA was absent in the spinal cord and mGluR3 mRNA was displayed only on glial cells in the white matter [21].
  • We have also investigated the function of mGluR2 in granule cells of the accessory olfactory bulb by combining immunoelectron-microscopic analysis with slice-patch recordings on the basis of the identification of a new agonist selective for this receptor subtype [22].

Associations of GRM2 with chemical compounds

  • Human metabotropic glutamate receptor 2 gene (GRM2): chromosomal sublocalization (3p21.1-p21.2) and genomic organization [16].
  • All the mGlu receptors except mGlu2 are activated by Ca(2+) and have serine instead of aspartic acid at this position, which suggests a critical role of this aspartic acid residue in the binding properties of this unique receptor [17].
  • Examples of these drugs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and LY379268 [23].
  • At human mGlu2 receptors, LY354740 produced > 90% suppression of forskolin-stimulated cAMP formation with an EC50 of 5.1 +/- 0.3 nM [24].
  • In particular, LY341495 is the most potent antagonist yet reported at mGlu2, 3 and 8 receptors [25].

Regulatory relationships of GRM2

  • LY354740 inhibition of forskolin-stimulated cAMP formation in human mGlu2 receptor-expressing cells was blocked by competitive mGlu receptor antagonists, including (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) and LY307452 ((2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-dioic acid) [24].
  • Each of these racemic methyl-substituted analogues displaced specific binding of the mGlu2/3 receptor antagonist (3)H-2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid ((3)H-LY341495) from membranes expressing mGlu2 or mGlu3 receptor subtypes [26].
  • After KA-induced status epilepticus, there was a significant elevation in mGluR1alpha protein expression within a select group of inhibitory interneurons of the CA1 stratum oriens-alveus that was enhanced with increasing number of neonatal seizures. mGluR2/3 and mGluR5 subtypes were unchanged [27].
  • The mGlu2/3 receptor agonist LY354740 suppresses immobilization stress-induced increase in rat prefrontal cortical BDNF mRNA expression [28].

Other interactions of GRM2

  • Using this functional assay, (R,S)-alpha-methyl-4-phosphonophenylglycine was found to have a similar KB value for mGluR2 and mGluR4 [29].
  • [3H]-LY341495 binding provides a useful way to further investigate regulation of receptor expression and pharmacological properties of mGlu2 and mGlu3 receptor subtypes in recombinant systems [18].
  • We report that mGluR2 and mGluR4, two receptors negatively coupled to adenylyl cyclase, activate PLC when coexpressed with G alpha 15, G alpha ql or G alpha qo [29].
  • At an approximate K(D) concentration for [3H]-LY341495 binding to human mGlu2 and mGlu3 receptors (1 nM), no appreciable specific binding of [3H-]LY341495 was found in membranes of cells expressing human mGlu1a, mGlu5a, mGlu4a, mGlu6, or mGlu7a receptors [18].
  • However, modest (approximately 20% of mGlu2/3) specific [3H]-LY341495 (1 nM) binding was observed in human mGlu8 expressing cells [18].

Analytical, diagnostic and therapeutic context of GRM2


  1. Glutamate metabotropic receptors as targets for drug therapy in epilepsy. Moldrich, R.X., Chapman, A.G., De Sarro, G., Meldrum, B.S. Eur. J. Pharmacol. (2003) [Pubmed]
  2. Pharmacological blockade of group II metabotropic glutamate receptors reduces the growth of glioma cells in vivo. Arcella, A., Carpinelli, G., Battaglia, G., D'Onofrio, M., Santoro, F., Ngomba, R.T., Bruno, V., Casolini, P., Giangaspero, F., Nicoletti, F. Neuro-oncology (2005) [Pubmed]
  3. Metabotropic glutamate receptor involvement in models of acute and persistent pain: prospects for the development of novel analgesics. Varney, M.A., Gereau, R.W. Current drug targets. CNS and neurological disorders. (2002) [Pubmed]
  4. Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis. Geurts, J.J., Wolswijk, G., Bö, L., van der Valk, P., Polman, C.H., Troost, D., Aronica, E. Brain (2003) [Pubmed]
  5. Metabotropic glutamate receptor 2/3 in the hippocampus of patients with mesial temporal lobe epilepsy, and of rats and mice after pilocarpine-induced status epilepticus. Tang, F.R., Chia, S.C., Chen, P.M., Gao, H., Lee, W.L., Yeo, T.S., Burgunder, J.M., Probst, A., Sim, M.K., Ling, E.A. Epilepsy Res. (2004) [Pubmed]
  6. Distribution and abundance of metabotropic glutamate receptor subtype 2 in rat brain revealed by [3H]LY354740 binding in vitro and quantitative radioautography: correlation with the sites of synthesis, expression, and agonist stimulation of [35S]GTPgammas binding. Richards, G., Messer, J., Malherbe, P., Pink, R., Brockhaus, M., Stadler, H., Wichmann, J., Schaffhauser, H., Mutel, V. J. Comp. Neurol. (2005) [Pubmed]
  7. The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. Cartmell, J., Monn, J.A., Schoepp, D.D. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  8. Transcriptional regulation of metabotropic glutamate receptor 2/3 expression by the NF-kappaB pathway in primary dorsal root ganglia neurons: a possible mechanism for the analgesic effect of L-acetylcarnitine. Chiechio, S., Copani, A., De Petris, L., Morales, M.E., Nicoletti, F., Gereau, R.W. Molecular pain [electronic resource] (2006) [Pubmed]
  9. An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats. Yoshimizu, T., Shimazaki, T., Ito, A., Chaki, S. Psychopharmacology (Berl.) (2006) [Pubmed]
  10. mGluR2 postsynaptically senses granule cell inputs at Golgi cell synapses. Watanabe, D., Nakanishi, S. Neuron (2003) [Pubmed]
  11. Inhibition of transient lower esophageal sphincter relaxation and gastroesophageal reflux by metabotropic glutamate receptor ligands. Frisby, C.L., Mattsson, J.P., Jensen, J.M., Lehmann, A., Dent, J., Blackshaw, L.A. Gastroenterology (2005) [Pubmed]
  12. mGluR2 acts through inhibitory G{alpha} subunits to regulate transmission and long-term plasticity at hippocampal mossy fiber-CA3 synapses. Nicholls, R.E., Zhang, X.L., Bailey, C.P., Conklin, B.R., Kandel, E.R., Stanton, P.K. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  13. Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death. Noh, K.M., Yokota, H., Mashiko, T., Castillo, P.E., Zukin, R.S., Bennett, M.V. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  14. Pharmacological blockade of mGlu2/3 metabotropic glutamate receptors reduces cell proliferation in cultured human glioma cells. D'Onofrio, M., Arcella, A., Bruno, V., Ngomba, R.T., Battaglia, G., Lombari, V., Ragona, G., Calogero, A., Nicoletti, F. J. Neurochem. (2003) [Pubmed]
  15. Alternative splicing of human metabotropic glutamate receptor 3. Sartorius, L.J., Nagappan, G., Lipska, B.K., Lu, B., Sei, Y., Ren-Patterson, R., Li, Z., Weinberger, D.R., Harrison, P.J. J. Neurochem. (2006) [Pubmed]
  16. Human metabotropic glutamate receptor 2 gene (GRM2): chromosomal sublocalization (3p21.1-p21.2) and genomic organization. Martí, S.B., Cichon, S., Propping, P., Nöthen, M. Am. J. Med. Genet. (2002) [Pubmed]
  17. Identification of essential residues involved in the glutamate binding pocket of the group II metabotropic glutamate receptor. Malherbe, P., Knoflach, F., Broger, C., Ohresser, S., Kratzeisen, C., Adam, G., Stadler, H., Kemp, J.A., Mutel, V. Mol. Pharmacol. (2001) [Pubmed]
  18. [3H]-LY341495 as a novel antagonist radioligand for group II metabotropic glutamate (mGlu) receptors: characterization of binding to membranes of mGlu receptor subtype expressing cells. Johnson, B.G., Wright, R.A., Arnold, M.B., Wheeler, W.J., Ornstein, P.L., Schoepp, D.D. Neuropharmacology (1999) [Pubmed]
  19. Reducing conditions differentially affect the functional and structural properties of group-I and -II metabotropic glutamate receptors. Copani, A., Romano, C., Di Giorgi Gerevini, V., Nicosia, A., Casabona, G., Storto, M., Mutel, V., Nicoletti, F. Brain Res. (2000) [Pubmed]
  20. (2S,1'S,2'R,3'R)-2(2'-Carboxy-3'-hydroxymethylcyclopropyl)glycine-[3H], a potent and selective radioligand for labeling group 2 and 3 metabotropic glutamate receptors. Wheeler, W.J., Clodfelter, D.K., Collado, I., Kulanthaivel, P., Pedregal, C., Stoddard, E.A., Wright, R.A., Schoepp, D.D. Bioorg. Med. Chem. Lett. (2005) [Pubmed]
  21. Expression of metabotropic glutamate receptor mRNAs in the human spinal cord: implications for selective vulnerability of spinal motor neurons in amyotrophic lateral sclerosis. Tomiyama, M., Kimura, T., Maeda, T., Tanaka, H., Furusawa, K., Kurahashi, K., Matsunaga, M. J. Neurol. Sci. (2001) [Pubmed]
  22. Molecular diversity of glutamate receptors and their physiological functions. Nakanishi, S., Masu, M., Bessho, Y., Nakajima, Y., Hayashi, Y., Shigemoto, R. EXS. (1994) [Pubmed]
  23. Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. Bruno, V., Battaglia, G., Copani, A., D'Onofrio, M., Di Iorio, P., De Blasi, A., Melchiorri, D., Flor, P.J., Nicoletti, F. J. Cereb. Blood Flow Metab. (2001) [Pubmed]
  24. LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Schoepp, D.D., Johnson, B.G., Wright, R.A., Salhoff, C.R., Mayne, N.G., Wu, S., Cockerman, S.L., Burnett, J.P., Belegaje, R., Bleakman, D., Monn, J.A. Neuropharmacology (1997) [Pubmed]
  25. LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Kingston, A.E., Ornstein, P.L., Wright, R.A., Johnson, B.G., Mayne, N.G., Burnett, J.P., Belagaje, R., Wu, S., Schoepp, D.D. Neuropharmacology (1998) [Pubmed]
  26. Methyl substitution of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate (LY354740) determines functional activity at metabotropic glutamate receptors: identification of a subtype selective mGlu2 receptor agonist. Dominguez, C., Prieto, L., Valli, M.J., Massey, S.M., Bures, M., Wright, R.A., Johnson, B.G., Andis, S.L., Kingston, A., Schoepp, D.D., Monn, J.A. J. Med. Chem. (2005) [Pubmed]
  27. Distinct regulation of metabotropic glutamate receptor (mGluR1 alpha) in the developing limbic system following multiple early-life seizures. Avallone, J., Gashi, E., Magrys, B., Friedman, L.K. Exp. Neurol. (2006) [Pubmed]
  28. The mGlu2/3 receptor agonist LY354740 suppresses immobilization stress-induced increase in rat prefrontal cortical BDNF mRNA expression. Lee, Y., Duman, R.S., Marek, G.J. Neurosci. Lett. (2006) [Pubmed]
  29. Coupling of metabotropic glutamate receptors 2 and 4 to G alpha 15, G alpha 16, and chimeric G alpha q/i proteins: characterization of new antagonists. Gomeza, J., Mary, S., Brabet, I., Parmentier, M.L., Restituito, S., Bockaert, J., Pin, J.P. Mol. Pharmacol. (1996) [Pubmed]
  30. Expression of metabotropic glutamate receptors in the rat and human testis. Storto, M., Sallese, M., Salvatore, L., Poulet, R., Condorelli, D.F., Dell'Albani, P., Marcello, M.F., Romeo, R., Piomboni, P., Barone, N., Nicoletti, F., Nicoletti, F., De Blasi, A. J. Endocrinol. (2001) [Pubmed]
  31. Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2. Flor, P.J., Lindauer, K., Püttner, I., Rüegg, D., Lukic, S., Knöpfel, T., Kuhn, R. Eur. J. Neurosci. (1995) [Pubmed]
  32. A role for noradrenergic transmission in the actions of phencyclidine and the antipsychotic and antistress effects of mGlu2/3 receptor agonists. Swanson, C.J., Schoepp, D.D. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
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