Metabotropic glutamate receptor 4 explained

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

Orthosteric

• Cinnabarinic acid, a tryptophan metabolite^[5]
• LSP1-2111: agonist^[6]
• LSP4-2022: agonist^[7]
• LSP2-9166: mixed agonist at mGluR₄ and mGluR₇

Positive allosteric modulators (PAMs)

• Foliglurax (PXT-002331, DT-1687)
• Tricyclic thiazolopyrazole derivative 22a: EC₅₀ = 9 nM, E_max = 120%^[8]
• ML-128: EC₅₀ = 240 nM, E_max = 182%^{[9] [10]}
• VU0652957 (AP-472) (Valiglurax)^[11]
• VU-0418506^{[12] [13]}
• VU-001171: EC₅₀ = 650 nM, E_max = 141%, 36-fold shift^[14]
• VU-0155041: subtype-selective PAM, intrinsic allosteric agonist activity, robust in-vivo activity^[15]
• PHCCC: PAM of mGluR4, negative allosteric modulator of mGluR1,^[16] direct agonist at mGluR6^[17]

Further reading

• Flor PJ, Lukic S, Rüegg D, Leonhardt T, Knöpfel T, Kuhn R . Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 4 . Neuropharmacology . 34 . 2 . 149–155 . February 1995 . 7617140 . 10.1016/0028-3908(94)00149-M . 31399907 .
• Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC . Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q . Genomics . 31 . 2 . 230–233 . January 1996 . 8824806 . 10.1006/geno.1996.0036 . free .
• Gomeza J, Mary S, Brabet I, Parmentier ML, Restituito S, Bockaert J, Pin JP . 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 . Molecular Pharmacology . 50 . 4 . 923–930 . October 1996 . 8863838 .
• Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi-Baez L, Ogryzko V, Avantaggiati ML, Pestell RG . p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation . The Journal of Biological Chemistry . 275 . 27 . 20853–20860 . July 2000 . 10779504 . 10.1074/jbc.M000660200 . free .
• Barbon A, Ferraboli S, Barlati S . Assignment of the human metabotropic glutamate receptor gene GRM4 to chromosome 6 band p21.3 by radiation hybrid mapping . Cytogenetics and Cell Genetics . 88 . 3–4 . 210 . 2000 . 10828590 . 10.1159/000015551 . 85055574 .
• Ohtsuki T, Toru M, Arinami T . Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia . Psychiatric Genetics . 11 . 2 . 79–83 . June 2001 . 11525421 . 10.1097/00041444-200106000-00004 . 752064 .
• Erdemir T, Bilican B, Oncel D, Goding CR, Yavuzer U . DNA damage-dependent interaction of the nuclear matrix protein C1D with Translin-associated factor X (TRAX) . Journal of Cell Science . 115 . Pt 1 . 207–216 . January 2002 . 11801738 . 10.1242/jcs.115.1.207 . free .
• Collard CD, Park KA, Montalto MC, Alapati S, Buras JA, Stahl GL, Colgan SP . Neutrophil-derived glutamate regulates vascular endothelial barrier function . The Journal of Biological Chemistry . 277 . 17 . 14801–14811 . April 2002 . 11847215 . 10.1074/jbc.M110557200 . free .
• Enz R . The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7 . FEBS Letters . 514 . 2–3 . 184–188 . March 2002 . 11943148 . 10.1016/S0014-5793(02)02361-X . 44474808 . free . 2002FEBSL.514..184E .
• Gaughan L, Logan IR, Cook S, Neal DE, Robson CN . Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor . The Journal of Biological Chemistry . 277 . 29 . 25904–25913 . July 2002 . 11994312 . 10.1074/jbc.M203423200 . free .
• Iacovelli L, Capobianco L, Iula M, Di Giorgi Gerevini V, Picascia A, Blahos J, Melchiorri D, Nicoletti F, De Blasi A . Regulation of mGlu4 metabotropic glutamate receptor signaling by type-2 G-protein coupled receptor kinase (GRK2) . Molecular Pharmacology . 65 . 5 . 1103–1110 . May 2004 . 15102938 . 10.1124/mol.65.5.1103 .
• Hermit MB, Greenwood JR, Bräuner-Osborne H . 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 . The Journal of Biological Chemistry . 279 . 33 . 34811–34817 . August 2004 . 15184361 . 10.1074/jbc.M404109200 . free .
• Yoo BC, Jeon E, Hong SH, Shin YK, Chang HJ, Park JG . Metabotropic glutamate receptor 4-mediated 5-Fluorouracil resistance in a human colon cancer cell line . Clinical Cancer Research . 10 . 12 Pt 1 . 4176–4184 . June 2004 . 15217955 . 10.1158/1078-0432.CCR-1114-03 . free .
• Chang HJ, Yoo BC, Lim SB, Jeong SY, Kim WH, Park JG . Metabotropic glutamate receptor 4 expression in colorectal carcinoma and its prognostic significance . Clinical Cancer Research . 11 . 9 . 3288–3295 . May 2005 . 15867225 . 10.1158/1078-0432.CCR-04-1912 . free .
• Mathiesen JM, Ramirez MT . The metabotropic glutamate receptor 4 is internalized and desensitized upon protein kinase C activation . British Journal of Pharmacology . 148 . 3 . 279–290 . June 2006 . 16582932 . 1751557 . 10.1038/sj.bjp.0706733 .
• Iacovelli L, Arcella A, Battaglia G, Pazzaglia S, Aronica E, Spinsanti P, Caruso A, De Smaele E, Saran A, Gulino A, D'Onofrio M, Giangaspero F, Nicoletti F . Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas . The Journal of Neuroscience . 26 . 32 . 8388–8397 . August 2006 . 16899734 . 6673797 . 10.1523/JNEUROSCI.2285-06.2006 . free .

Notes and References

1. Makoff A, Lelchuk R, Oxer M, Harrington K, Emson P . Molecular characterization and localization of human metabotropic glutamate receptor type 4 . Brain Research. Molecular Brain Research . 37 . 1–2 . 239–248 . April 1996 . 8738157 . 10.1016/0169-328X(95)00321-I .
2. Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR, Johnson BG, Schoepp DD, Belagaje RM . Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells . Brain Research. Molecular Brain Research . 53 . 1–2 . 88–97 . January 1998 . 9473604 . 10.1016/S0169-328X(97)00277-5 .
3. Web site: Entrez Gene: GRM4 glutamate receptor, metabotropic 4.
4. Chaudhari N, Landin AM, Roper SD . A metabotropic glutamate receptor variant functions as a taste receptor . Nature Neuroscience . 3 . 2 . 113–119 . February 2000 . 10649565 . 10.1038/72053 . 16650588 .
5. Fazio F, Lionetto L, Molinaro G, Bertrand HO, Acher F, Ngomba RT, Notartomaso S, Curini M, Rosati O, Scarselli P, Di Marco R, Battaglia G, Bruno V, Simmaco M, Pin JP, Nicoletti F, Goudet C . Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors . Molecular Pharmacology . 81 . 5 . 643–656 . May 2012 . 22311707 . 10.1124/mol.111.074765 . 6735807 .
6. Wierońska JM, Stachowicz K, Pałucha-Poniewiera A, Acher F, Brański P, Pilc A . 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 . 627–634 . December 2010 . 20713068 . 10.1016/j.neuropharm.2010.08.008 . 5171741 .
7. Goudet C, Vilar B, Courtiol T, Deltheil T, Bessiron T, Brabet I, Oueslati N, Rigault D, Bertrand HO, McLean H, Daniel H, Amalric M, Acher F, Pin JP . A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential . FASEB Journal . 26 . 4 . 1682–1693 . April 2012 . 22223752 . 10.1096/fj.11-195941 . 22662090 . free .
8. Hong SP, Liu KG, Ma G, Sabio M, Uberti MA, Bacolod MD, Peterson J, Zou ZZ, Robichaud AJ, Doller D . Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators . Journal of Medicinal Chemistry . 54 . 14 . 5070–5081 . July 2011 . 21688779 . 10.1021/jm200290z .
9. Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator . Probe Reports from the NIH Molecular Libraries Program [Internet] . 2010 . 21433377 . Hopkins CR, Niswender CM, Lewis LM, Weaver CD, Lindsley CW .
10. Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon UN, Zamorano R, Conn PJ, Lindsley CW, Hopkins CR . Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs) . Journal of Medicinal Chemistry . 52 . 14 . 4115–4118 . July 2009 . 19469556 . 2765192 . 10.1021/jm9005065 .
11. Panarese JD, Engers DW, Wu YJ, Bronson JJ, Macor JE, Chun A, Rodriguez AL, Felts AS, Engers JL, Loch MT, Emmitte KA, Castelhano AL, Kates MJ, Nader MA, Jones CK, Blobaum AL, Conn PJ, Niswender CM, Hopkins CR, Lindsley CW . Discovery of VU2957 (Valiglurax): An mGlu₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease . ACS Medicinal Chemistry Letters . 10 . 3 . 255–260 . March 2019 . 30891122 . 6421540 . 10.1021/acsmedchemlett.8b00426 .
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13. Engers DW, Blobaum AL, Gogliotti RD, Cheung YY, Salovich JM, Garcia-Barrantes PM, Daniels JS, Morrison R, Jones CK, Soars MG, Zhuo X, Hurley J, Macor JE, Bronson JJ, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR . Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4) . ACS Chemical Neuroscience . 7 . 9 . 1192–1200 . September 2016 . 27075300 . 5031509 . 10.1021/acschemneuro.6b00035 .
14. Williams R, Niswender CM, Luo Q, Le U, Conn PJ, Lindsley CW . Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead . Bioorganic & Medicinal Chemistry Letters . 19 . 3 . 962–966 . February 2009 . 19097893 . 3787871 . 10.1016/j.bmcl.2008.11.104 .
15. 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 . Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4 . Molecular Pharmacology . 74 . 5 . 1345–1358 . November 2008 . 18664603 . 2574552 . 10.1124/mol.108.049551 .
16. Watkins JC, Jane DE . The glutamate story . British Journal of Pharmacology . 147 . Suppl 1 . S100–S108 . January 2006 . 16402093 . 1760733 . 10.1038/sj.bjp.0706444 .
17. Beqollari D, Kammermeier PJ . 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 . July 2008 . 18593581 . 10.1016/j.ejphar.2008.06.054 .