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Metabotropic glutamate receptor 4

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(Redirected fromGRM4)
GRM4
Identifiers
AliasesGRM4,GPRC1D, MGLUR4, mGlu4, glutamate metabotropic receptor 4
External IDsOMIM:604100;MGI:1351341;HomoloGene:20230;GeneCards:GRM4;OMA:GRM4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2914

268934

Ensembl

ENSG00000124493

ENSMUSG00000063239

UniProt

Q14833

Q68EF4

RefSeq (mRNA)

NM_001013385
NM_001291045
NM_001360192
NM_001379317

RefSeq (protein)

NP_001013403
NP_001277974
NP_001347121

Location (UCSC)Chr 6: 34.02 – 34.16 MbChr 17: 27.64 – 27.74 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Metabotropic glutamate receptor 4is aproteinthat in humans is encoded by theGRM4gene.[5][6][7]

Together with GRM6, GRM7 and GRM8 it belongs togroup IIIof themetabotropic glutamate receptorfamily. Group III receptors are linked to the inhibition of the cyclic AMP cascade.[7] Activation of GRM4 has potential therapeutic benefits in the treatment ofparkinson's disease.Splice variant"taste-GRM4" is involved in the perception ofumamitaste.[8]

Ligands

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Orthosteric

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Positive allosteric modulators (PAMs)

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  • Foliglurax(PXT-002331, DT-1687)
  • Tricyclic thiazolopyrazole derivative 22a: EC50= 9 nM, Emax= 120%[12]
  • ML-128:EC50= 240 nM, Emax= 182%[13][14]
  • VU0652957 (AP-472) (Valiglurax)[15]
  • VU-0418506[16][17]
  • VU-001171: EC50= 650 nM, Emax= 141%, 36-fold shift[18]
  • VU-0155041: subtype-selective PAM, intrinsic allosteric agonist activity, robust in-vivo activity[19]
  • PHCCC:PAM of mGluR4, negative allosteric modulator ofmGluR1,[20]direct agonist atmGluR6[21]

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000124493–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000063239–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Makoff A, Lelchuk R, Oxer M, Harrington K, Emson P (Apr 1996). "Molecular characterization and localization of human metabotropic glutamate receptor type 4".Brain Research. Molecular Brain Research.37(1–2): 239–48.doi:10.1016/0169-328X(95)00321-I.PMID8738157.
  6. ^Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR, Johnson BG, Schoepp DD, Belagaje RM (Jan 1998). "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.doi:10.1016/S0169-328X(97)00277-5.PMID9473604.
  7. ^ab"Entrez Gene: GRM4 glutamate receptor, metabotropic 4".
  8. ^Chaudhari N, Landin AM, Roper SD (Feb 2000). "A metabotropic glutamate receptor variant functions as a taste receptor".Nature Neuroscience.3(2): 113–9.doi:10.1038/72053.PMID10649565.S2CID16650588.
  9. ^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 (May 2012). "Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors".Molecular Pharmacology.81(5): 643–56.doi:10.1124/mol.111.074765.PMID22311707.S2CID6735807.
  10. ^Wierońska JM, Stachowicz K, Pałucha-Poniewiera A, Acher F, Brański P, Pilc A (Dec 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.PMID20713068.S2CID5171741.
  11. ^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 (2012)."A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential".FASEB J.26(4): 1682–93.doi:10.1096/fj.11-195941.PMID22223752.S2CID22662090.
  12. ^Hong SP, Liu KG, Ma G, Sabio M, Uberti MA, Bacolod MD, Peterson J, Zou ZZ, Robichaud AJ, Doller D (Jul 2011). "Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators".Journal of Medicinal Chemistry.54(14): 5070–81.doi:10.1021/jm200290z.PMID21688779.
  13. ^Hopkins CR, Niswender CM, Lewis LM, Weaver CD, Lindsley CW (2010). "Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator".Probe Reports from the NIH Molecular Libraries Program [Internet].PMID21433377.
  14. ^Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon UN, Zamorano R, Conn PJ, Lindsley CW, Hopkins CR (Jul 2009)."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): 4115–8.doi:10.1021/jm9005065.PMC2765192.PMID19469556.
  15. ^Panarese JD, Engers DW, Wu YJ, Bronson JJ, Macor JE, Chun A, Rodriguez AL, Felts AS, Engers JL, Loch MT, Emmitte KA (2019-03-14)."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.doi:10.1021/acsmedchemlett.8b00426.ISSN1948-5875.PMC6421540.PMID30891122.
  16. ^Niswender CM, Jones CK, Lin X, Bubser M, Thompson Gray A, Blobaum AL, Engers DW, Rodriguez AL, Loch MT, Daniels JS, Lindsley CW, Hopkins CR, Javitch JA, Conn PJ (2016)."Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers".ACS Chem Neurosci.7(9): 1201–11.doi:10.1021/acschemneuro.6b00036.PMC5073817.PMID27441572.
  17. ^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 (2016)."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 Chem Neurosci.7(9): 1192–200.doi:10.1021/acschemneuro.6b00035.PMC5031509.PMID27075300.
  18. ^Williams R, Niswender CM, Luo Q, Le U, Conn PJ, Lindsley CW (Feb 2009)."Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead".Bioorganic & Medicinal Chemistry Letters.19(3): 962–6.doi:10.1016/j.bmcl.2008.11.104.PMC3787871.PMID19097893.
  19. ^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 (Nov 2008)."Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4".Molecular Pharmacology.74(5): 1345–58.doi:10.1124/mol.108.049551.PMC2574552.PMID18664603.
  20. ^Watkins JC, Jane DE (Jan 2006)."The glutamate story".British Journal of Pharmacology.147(Suppl 1): S100-8.doi:10.1038/sj.bjp.0706444.PMC1760733.PMID16402093.
  21. ^Beqollari D, Kammermeier PJ (Jul 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.PMID18593581.

Further reading

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This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.

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