Wikipedia

Metabotropic glutamate receptor 4

(Redirected from MGluR4)

Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.[5][6][7]

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
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[7] 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.[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 of mGluR1,[20] direct agonist at mGluR6[21]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000124493 – Ensembl, May 2017
  2. ^ a b c GRCm38: 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 (April 1996). "Molecular characterization and localization of human metabotropic glutamate receptor type 4". Brain Research. Molecular Brain Research. 37 (1–2): 239–248. doi:10.1016/0169-328X(95)00321-I. PMID 8738157.
  6. ^ Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR, et al. (January 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. PMID 9473604.
  7. ^ a b "Entrez Gene: GRM4 glutamate receptor, metabotropic 4".
  8. ^ Chaudhari N, Landin AM, Roper SD (February 2000). "A metabotropic glutamate receptor variant functions as a taste receptor". Nature Neuroscience. 3 (2): 113–119. doi:10.1038/72053. PMID 10649565. S2CID 16650588.
  9. ^ Fazio F, Lionetto L, Molinaro G, Bertrand HO, Acher F, Ngomba RT, et al. (May 2012). "Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors". Molecular Pharmacology. 81 (5): 643–656. doi:10.1124/mol.111.074765. PMID 22311707. S2CID 6735807.
  10. ^ 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): 627–634. doi:10.1016/j.neuropharm.2010.08.008. PMID 20713068. S2CID 5171741.
  11. ^ Goudet C, Vilar B, Courtiol T, Deltheil T, Bessiron T, Brabet I, et al. (April 2012). "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. doi:10.1096/fj.11-195941. PMID 22223752. S2CID 22662090.
  12. ^ Hong SP, Liu KG, Ma G, Sabio M, Uberti MA, Bacolod MD, et al. (July 2011). "Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators". Journal of Medicinal Chemistry. 54 (14): 5070–5081. doi:10.1021/jm200290z. PMID 21688779.
  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]. PMID 21433377.
  14. ^ Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon UN, Zamorano R, 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)". Journal of Medicinal Chemistry. 52 (14): 4115–4118. doi:10.1021/jm9005065. PMC 2765192. PMID 19469556.
  15. ^ Panarese JD, Engers DW, Wu YJ, Bronson JJ, Macor JE, Chun A, et al. (March 2019). "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. PMC 6421540. PMID 30891122.
  16. ^ Niswender CM, Jones CK, Lin X, Bubser M, Thompson Gray A, Blobaum AL, et al. (September 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 Chemical Neuroscience. 7 (9): 1201–1211. doi:10.1021/acschemneuro.6b00036. PMC 5073817. PMID 27441572.
  17. ^ Engers DW, Blobaum AL, Gogliotti RD, Cheung YY, Salovich JM, Garcia-Barrantes PM, et al. (September 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 Chemical Neuroscience. 7 (9): 1192–1200. doi:10.1021/acschemneuro.6b00035. PMC 5031509. PMID 27075300.
  18. ^ 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". Bioorganic & Medicinal Chemistry Letters. 19 (3): 962–966. doi:10.1016/j.bmcl.2008.11.104. PMC 3787871. PMID 19097893.
  19. ^ Niswender CM, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, et al. (November 2008). "Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4". Molecular Pharmacology. 74 (5): 1345–1358. doi:10.1124/mol.108.049551. PMC 2574552. PMID 18664603.
  20. ^ Watkins JC, Jane DE (January 2006). "The glutamate story". British Journal of Pharmacology. 147 (Suppl 1): S100–S108. doi:10.1038/sj.bjp.0706444. PMC 1760733. PMID 16402093.
  21. ^ 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". European Journal of Pharmacology. 589 (1–3): 49–52. doi:10.1016/j.ejphar.2008.06.054. PMID 18593581.

Further reading

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

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