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Gene Review

GRM4  -  glutamate receptor, metabotropic 4

Homo sapiens

Synonyms: GPRC1D, MGLUR4, Metabotropic glutamate receptor 4, mGlu4, mGluR4
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Disease relevance of GRM4


Psychiatry related information on GRM4

  • Results of our studies indicate that a combined administration positive allosteric modulation of mGlu4 receptor and agonists of group III mGlu receptors may be a promising target in the future treatment of depressive disorder [4].

High impact information on GRM4

  • As mGluR4 represents an inhibitory class III mGluR associated with the reduction of intracellular cyclic AMP levels and calcium influx, we have analyzed the regional and cellular expression of mGluR4 in surgical hippocampal specimens obtained from patients with TLE by using immunohistochemistry and in situ hybridization [5].
  • Although the hippocampi of control specimens (n = 11) were almost devoid of mGluR4 immunolabeling, all TLE specimens (n = 35) showed a striking up-regulation of mGluR4 immunoreactivity, in particular within the dentate gyrus [5].
  • In particular, the mutations K74Y and K317R induced dramatic triple-order-of-magnitude increases in the affinity of ibotenic acid at mGluR4, making the affinity equivalent to that of mGluR1 [6].
  • Indeed, the mGlu2 and mGlu4 and -8 receptors can discriminate between alpha subunits that differ at the level of their C-terminal end only (such as Gqo and Gqz) [7].
  • To that aim, we analyzed the coupling properties of mGlu2 and mGlu4 or -8 receptors and chimeras containing the i2 loop of the converse receptor to G-protein alpha subunits that only differ by their C termini (Gqo,Gqz, and their point mutants) [7].

Biological context of GRM4


Anatomical context of GRM4


Associations of GRM4 with chemical compounds

  • Furthermore, the affinity of quisqualic acid at mGluR4 was increased to the same level as mGluR1 by the two double mutations, K74Y/K317R and K74Y/E287G [6].
  • LY354740 had no agonist or antagonist activities at cells expressing human mGlu4 or mGlu7 (group III mGlu receptors) (EC50 > 100,000 nM) [13].
  • The subtypes of group 2 (mGluR2 and 3) and group 3 (mGluR4, 6 7 and 8) inhibit adenylate cyclase and, thereby, mediate a decrease in cAMP concentration [14].
  • Transfection of GqGi3 into previously validated stable CHO cell lines expressing mGluR2 or mGluR4 allowed for the selection of new double transfectants in which application of L-glutamate and other mGluR agonists resulted in calcium coupling with a high signal:noise ratio (maximal changes in relative fluorescence units up to 20,000) [15].
  • To get an insight into the bioactive conformation of glutamic acid and its topological environment at the mGluR4 binding site, a pharmacophore model was constructed using molecular modeling [16].

Other interactions of GRM4

  • Using this functional assay, (R,S)-alpha-methyl-4-phosphonophenylglycine was found to have a similar KB value for mGluR2 and mGluR4 [17].
  • We sequenced between 1865 (mGluR8a) and 3697 (mGluR1) total nucleotides for each macaque gene and obtained complete coding sequences for GluR1-7, mGluR3 and mGluR4 [18].
  • Signals for mGluR1 and mGluR5 were enriched in the dorsal horn, while mGluR4 mRNA was abundant in the ventral horn [19].
  • 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 [17].
  • A comparison with the corresponding human sequences reveal that the coding region of macaque GluR6 demonstrates the highest homology with only 26 nucleotide substitutions (99% homology), while mGluR4 demonstrates the lowest with 68 substitutions (97.5%) [18].

Analytical, diagnostic and therapeutic context of GRM4


  1. 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]
  2. Metabotropic glutamate receptor 4 expression in colorectal carcinoma and its prognostic significance. Chang, H.J., Yoo, B.C., Lim, S.B., Jeong, S.Y., Kim, W.H., Park, J.G. Clin. Cancer Res. (2005) [Pubmed]
  3. Expression patterns of Group III metabotropic glutamate receptors mGluR4 and mGluR8 in multiple sclerosis lesions. Geurts, J.J., Wolswijk, G., Bö, L., Redeker, S., Ramkema, M., Troost, D., Aronica, E. J. Neuroimmunol. (2005) [Pubmed]
  4. Combined administration of PHCCC, a positive allosteric modulator of mGlu4 receptors and ACPT-I, mGlu III receptor agonist evokes antidepressant-like effects in rats. Kłak, K., Pałucha, A., Brański, P., Sowa, M., Pilc, A. Amino Acids (2007) [Pubmed]
  5. Up-regulation of the metabotropic glutamate receptor mGluR4 in hippocampal neurons with reduced seizure vulnerability. Lie, A.A., Becker, A., Behle, K., Beck, H., Malitschek, B., Conn, P.J., Kuhn, R., Nitsch, R., Plaschke, M., Schramm, J., Elger, C.E., Wiestler, O.D., Blümcke, I. Ann. Neurol. (2000) [Pubmed]
  6. Mutation-induced quisqualic acid and ibotenic acid affinity at the metabotropic glutamate receptor subtype 4: ligand selectivity results from a synergy of several amino acid residues. Hermit, M.B., Greenwood, J.R., Bräuner-Osborne, H. J. Biol. Chem. (2004) [Pubmed]
  7. The second intracellular loop of metabotropic glutamate receptors recognizes C termini of G-protein alpha-subunits. Havlickova, M., Blahos, J., Brabet, I., Liu, J., Hruskova, B., Prézeau, L., Pin, J.P. J. Biol. Chem. (2003) [Pubmed]
  8. Assignment of the human metabotropic glutamate receptor gene GRM4 to chromosome 6 band p21.3 by radiation hybrid mapping. Barbon, A., Ferraboli, S., Barlati, S. Cytogenet. Cell Genet. (2000) [Pubmed]
  9. 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]
  10. Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells. Wu, S., Wright, R.A., Rockey, P.K., Burgett, S.G., Arnold, J.S., Rosteck, P.R., Johnson, B.G., Schoepp, D.D., Belagaje, R.M. Brain Res. Mol. Brain Res. (1998) [Pubmed]
  11. Neutrophil-derived glutamate regulates vascular endothelial barrier function. Collard, C.D., Park, K.A., Montalto, M.C., Alapati, S., Buras, J.A., Stahl, G.L., Colgan, S.P. J. Biol. Chem. (2002) [Pubmed]
  12. Activation of metabotropic glutamate receptors delays apoptosis of chick embryonic motor neurons in vitro. Anneser, J.M., Horstmann, S., Weydt, P., Borasio, G.D. Neuroreport (1998) [Pubmed]
  13. 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]
  14. Metabotropic glutamate receptors in the cerebellum with a focus on their function in Purkinje cells. Knöpfel, T., Grandes, P. Cerebellum (2002) [Pubmed]
  15. Functional calcium coupling with the human metabotropic glutamate receptor subtypes 2 and 4 by stable co-expression with a calcium pathway facilitating G-protein chimera in Chinese hamster ovary cells. Kowal, D., Nawoschik, S., Ochalski, R., Dunlop, J. Biochem. Pharmacol. (2003) [Pubmed]
  16. Extended glutamate activates metabotropic receptor types 1, 2 and 4: selective features at mGluR4 binding site. Bessis, A.S., Jullian, N., Coudert, E., Pin, J.P., Acher, F. Neuropharmacology (1999) [Pubmed]
  17. 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]
  18. Expression and sequences of genes encoding glutamate receptors and transporters in primate retina determined using 3'-end amplification polymerase chain reaction. Hanna, M.C., Calkins, D.J. Mol. Vis. (2006) [Pubmed]
  19. 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]
  20. Molecular determinants of high affinity binding to group III metabotropic glutamate receptors. Rosemond, E., Peltekova, V., Naples, M., Thøgersen, H., Hampson, D.R. J. Biol. Chem. (2002) [Pubmed]
  21. Molecular characterization and localization of human metabotropic glutamate receptor type 4. Makoff, A., Lelchuk, R., Oxer, M., Harrington, K., Emson, P. Brain Res. Mol. Brain Res. (1996) [Pubmed]
  22. Constraints on proper folding of the amino terminal domains of group III metabotropic glutamate receptors. Peltekova, V., Han, G., Soleymanlou, N., Hampson, D.R. Brain Res. Mol. Brain Res. (2000) [Pubmed]
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