Metabotropic glutamate receptor 4

Glutamate receptor, metabotropic 4
Identifiers
Symbols	GRM4; GPRC1D; MGC177594; MGLUR4; mGlu4
External IDs	OMIM: 604100 MGI: 1351341 HomoloGene: 20230 GeneCards: GRM4 Gene
Gene Ontology Molecular function • receptor activity • G-protein coupled receptor activity • glutamate receptor activity Cellular component • intracellular • plasma membrane • integral to plasma membrane • cytoplasmic vesicle Biological process • activation of MAPK activity • G-protein coupled receptor protein signaling pathway • inhibition of adenylate cyclase activity by metabotropic glutamate receptor signaling pathway • synaptic transmission • neurotransmitter secretion • positive regulation of MAPKKK cascade • neuroprotection Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2914	268934
Ensembl	ENSG00000124493	ENSMUSG00000063239
UniProt	Q14833	Q68EF4
RefSeq (mRNA)	NM_000841	NM_001013385.1
RefSeq (protein)	NP_000832	NP_001013403.1
Location (UCSC)	Chr 6: 33.99 – 34.12 Mb	Chr 17: 27.56 – 27.65 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. "Taste-GRM4" is involved in the perception of umami.

Ligands

Orthosteric

• LSP1-2111^[4], LSP1-3081: agonists

Positive allosteric modulators (PAMs)

• Tricyclic thiazolopyrazole derivative 22a: EC₅₀ = 9 nM, E_max = 120%^[5]
• ML-128: EC₅₀ = 240 nM, E_max = 182%^[6][7]
• VU-001171: EC₅₀ = 650 nM, E_max = 141%, 36-fold shift^[8]
• VU-0155041: subtype-selective PAM, intrinsic allosteric agonist activity, robust in-vivo activity^[9]
• PHCCC: PAM of mGluR4, negative allosteric modulator of mGluR1,^[10] direct agonist at mGluR6^[11]

3d model of compound 22a (Hong 2011)

References

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". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2914. 
4. ^ PMID 20713068
5. ^ PMID 21688779
6. ^ PMID 21433377
7. ^ Engers DW, Niswender CM, Weaver CD, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2765192. 
8. ^ Williams R, Niswender CM, Luo Q, Le U, Conn PJ, Lindsley CW (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. PMID 19097893. 
9. ^ Niswender CM, Johnson KA, Weaver CD, et al. (2008). "Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4". Mol. Pharmacol. 74 (5): 1345. doi:10.1124/mol.108.049551. PMC 2574552. PMID 18664603. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2574552. 
10. ^ Watkins JC, Jane DE (2006). "The glutamate story". British journal of pharmacology 147 Suppl 1: S100–8. doi:10.1038/sj.bjp.0706444. PMC 1760733. PMID 16402093. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1760733. 
11. ^ Beqollari D, Kammermeier PJ (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". European journal of pharmacology 589 (1-3): 49–52. doi:10.1016/j.ejphar.2008.06.054. PMID 18593581. 

External links

• "Metabotropic Glutamate Receptors: mGlu₄". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2274. 

Further reading

• 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1751557. 
• 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.

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