Metabotropic glutamate receptor 4

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Glutamate receptor, metabotropic 4
Identifiers
Symbols GRM4 ; GPRC1D; MGLUR4; mGlu4
External IDs OMIM604100 MGI1351341 HomoloGene20230 IUPHAR: mGlu4 ChEMBL: 2736 GeneCards: GRM4 Gene
RNA expression pattern
PBB GE GRM4 210234 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2914 268934
Ensembl ENSG00000124493 ENSMUSG00000063239
UniProt Q14833 Q68EF4
RefSeq (mRNA) NM_000841 NM_001013385
RefSeq (protein) NP_000832 NP_001013403
Location (UCSC) Chr 6:
33.99 – 34.12 Mb
Chr 17:
27.42 – 27.51 Mb
PubMed search [1] [2]

Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.[1][2][3]

Together with GRM6, GRM7 and GRM8 it belongs to group III of the metabotropic glutamate receptor family. Group III receptors are linked to the inhibition of the cyclic AMP cascade.[3] Activation of GRM4 has potential therapeutic benefits in the treatment of parkinson's disease. Splice variant "taste-GRM4" is involved in the perception of umami taste.[4]


Ligands[edit]

Orthosteric[edit]

  • LSP1-2111,[5] LSP1-3081: agonists

Positive allosteric modulators (PAMs)[edit]

  • Tricyclic thiazolopyrazole derivative 22a: EC50 = 9 nM, Emax = 120%[6]
  • ML-128: EC50 = 240 nM, Emax = 182%[7][8]
  • VU-001171: EC50 = 650 nM, Emax = 141%, 36-fold shift[9]
  • VU-0155041: subtype-selective PAM, intrinsic allosteric agonist activity, robust in-vivo activity[10]
  • PHCCC: PAM of mGluR4, negative allosteric modulator of mGluR1,[11] direct agonist at mGluR6[12]
3d model of compound 22a (Hong 2011)

References[edit]

  1. ^ Makoff A, Lelchuk R, Oxer M, Harrington K, Emson P (Dec 1996). "Molecular characterization and localization of human metabotropic glutamate receptor type 4". Brain Res Mol Brain Res 37 (1-2): 239–48. doi:10.1016/0169-328X(95)00321-I. PMID 8738157. 
  2. ^ Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR Jr, Johnson BG, Schoepp DD, Belagaje RM (Apr 1998). "Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells". Brain Res Mol Brain Res 53 (1-2): 88–97. doi:10.1016/S0169-328X(97)00277-5. PMID 9473604. 
  3. ^ a b "Entrez Gene: GRM4 glutamate receptor, metabotropic 4". 
  4. ^ Chaudhari N, Landin AM, Roper SD (February 2000). "A metabotropic glutamate receptor variant functions as a taste receptor". Nat. Neurosci. 3 (2): 113–9. doi:10.1038/72053. PMID 10649565. 
  5. ^ Wierońska JM, Stachowicz K, Pałucha-Poniewiera A, Acher F, Brański P, Pilc A (December 2010). "Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems". Neuropharmacology 59 (7-8): 627–34. doi:10.1016/j.neuropharm.2010.08.008. PMID 20713068. 
  6. ^ Hong SP, Liu KG, Ma G, Sabio M, Uberti MA, Bacolod MD, Peterson J, Zou ZZ, Robichaud AJ, Doller D (July 2011). "Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators". J. Med. Chem. 54 (14): 5070–81. doi:10.1021/jm200290z. PMID 21688779. 
  7. ^ Hopkins CR, Niswender CM, Lewis LM, Weaver CD, Lindsley CW. Probe Reports from the NIH Molecular Libraries Program [Internet]. PMID 21433377. 
  8. ^ Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon UN, Zamorano R, Conn PJ, Lindsley CW, Hopkins CR (July 2009). "Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs)". J. Med. Chem. 52 (14): 4115–8. doi:10.1021/jm9005065. PMC 2765192. PMID 19469556. 
  9. ^ Williams R, Niswender CM, Luo Q, Le U, Conn PJ, Lindsley CW (February 2009). "Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead". Bioorg. Med. Chem. Lett. 19 (3): 962–6. doi:10.1016/j.bmcl.2008.11.104. PMC 3787871. PMID 19097893. 
  10. ^ Niswender CM, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, Rodriguez AL, Marlo JE, de Paulis T, Thompson AD, Days EL, Nalywajko T, Austin CA, Williams MB, Ayala JE, Williams R, Lindsley CW, Conn PJ (November 2008). "Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4". Mol. Pharmacol. 74 (5): 1345–58. doi:10.1124/mol.108.049551. PMC 2574552. PMID 18664603. 
  11. ^ Watkins JC, Jane DE (January 2006). "The glutamate story". Br. J. Pharmacol. 147 Suppl 1: S100–8. doi:10.1038/sj.bjp.0706444. PMC 1760733. PMID 16402093. 
  12. ^ Beqollari D, Kammermeier PJ (July 2008). "The mGlu(4) receptor allosteric modulator N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide acts as a direct agonist at mGlu(6) receptors". Eur. J. Pharmacol. 589 (1-3): 49–52. doi:10.1016/j.ejphar.2008.06.054. PMID 18593581. 

External links[edit]

Further reading[edit]

  • Flor PJ, Lukic S, Rüegg D, et al. (1995). "Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 4.". Neuropharmacology 34 (2): 149–55. doi:10.1016/0028-3908(94)00149-M. PMID 7617140. 
  • Scherer SW, Duvoisin RM, Kuhn R, et al. (1997). "Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q.". Genomics 31 (2): 230–3. doi:10.1006/geno.1996.0036. PMID 8824806. 
  • Gomeza J, Mary S, Brabet I, et al. (1996). "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.". Mol. Pharmacol. 50 (4): 923–30. PMID 8863838. 
  • Fu M, Wang C, Reutens AT, et al. (2000). "p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation.". J. Biol. Chem. 275 (27): 20853–60. doi:10.1074/jbc.M000660200. PMID 10779504. 
  • Barbon A, Ferraboli S, Barlati S (2000). "Assignment of the human metabotropic glutamate receptor gene GRM4 to chromosome 6 band p21.3 by radiation hybrid mapping.". Cytogenet. Cell Genet. 88 (3-4): 210. doi:10.1159/000015551. PMID 10828590. 
  • Ohtsuki T, Toru M, Arinami T (2002). "Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia.". Psychiatr. Genet. 11 (2): 79–83. doi:10.1097/00041444-200106000-00004. PMID 11525421. 
  • Erdemir T, Bilican B, Oncel D, et al. (2002). "DNA damage-dependent interaction of the nuclear matrix protein C1D with Translin-associated factor X (TRAX).". J. Cell. Sci. 115 (Pt 1): 207–16. PMID 11801738. 
  • Collard CD, Park KA, Montalto MC, et al. (2002). "Neutrophil-derived glutamate regulates vascular endothelial barrier function.". J. Biol. Chem. 277 (17): 14801–11. doi:10.1074/jbc.M110557200. PMID 11847215. 
  • Enz R (2002). "The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7.". FEBS Lett. 514 (2-3): 184–8. doi:10.1016/S0014-5793(02)02361-X. PMID 11943148. 
  • Gaughan L, Logan IR, Cook S, et al. (2002). "Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor.". J. Biol. Chem. 277 (29): 25904–13. doi:10.1074/jbc.M203423200. PMID 11994312. 
  • Mungall AJ, Palmer SA, Sims SK, et al. (2003). "The DNA sequence and analysis of human chromosome 6.". Nature 425 (6960): 805–11. doi:10.1038/nature02055. PMID 14574404. 
  • Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039. 
  • Iacovelli L, Capobianco L, Iula M, et al. (2004). "Regulation of mGlu4 metabotropic glutamate receptor signaling by type-2 G-protein coupled receptor kinase (GRK2).". Mol. Pharmacol. 65 (5): 1103–10. doi:10.1124/mol.65.5.1103. PMID 15102938. 
  • Hermit MB, Greenwood JR, Bräuner-Osborne H (2004). "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.". J. Biol. Chem. 279 (33): 34811–7. doi:10.1074/jbc.M404109200. PMID 15184361. 
  • Yoo BC, Jeon E, Hong SH, et al. (2005). "Metabotropic glutamate receptor 4-mediated 5-Fluorouracil resistance in a human colon cancer cell line.". Clin. Cancer Res. 10 (12 Pt 1): 4176–84. doi:10.1158/1078-0432.CCR-1114-03. PMID 15217955. 
  • Chang HJ, Yoo BC, Lim SB, et al. (2005). "Metabotropic glutamate receptor 4 expression in colorectal carcinoma and its prognostic significance.". Clin. Cancer Res. 11 (9): 3288–95. doi:10.1158/1078-0432.CCR-04-1912. PMID 15867225. 
  • Mathiesen JM, Ramirez MT (2006). "The metabotropic glutamate receptor 4 is internalized and desensitized upon protein kinase C activation.". Br. J. Pharmacol. 148 (3): 279–90. doi:10.1038/sj.bjp.0706733. PMC 1751557. PMID 16582932. 
  • Iacovelli L, Arcella A, Battaglia G, et al. (2006). "Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas.". J. Neurosci. 26 (32): 8388–97. doi:10.1523/JNEUROSCI.2285-06.2006. PMID 16899734. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.