Metabotropic glutamate receptor 4

from Wikipedia, the free encyclopedia
Metabotropic glutamate receptor 4
other names

GRM4, mGluR4

Properties of human protein
Mass / length primary structure 912 amino acids , 101,868 Da
Identifier
External IDs
Orthologue
human House mouse
Entrez 2914 268934
Ensemble ENSG00000124493 ENSMUSG00000063239
UniProt Q14833 Q68EF4
Refseq (mRNA) NM_000841.3 NM_001013385.2
Refseq (protein) NP_000832.1 NP_001013403.1
Gene locus
PubMed search 2914 268934

Metabotropic glutamate receptor 4 (GRM 4, mGluR4) is a protein from the group of metabotropic glutamate receptors .

properties

The metabotropic glutamate receptor 4 is a G protein-coupled receptor . It is produced in larger quantities in the cerebellum and in smaller quantities in the hippocampus , hypothalamus and thalamus , but not in the liver . Together with mGluR6 , mGluR7 and mGluR8 it forms group III of the metabotropic glutamate receptors. After binding of glutamate , a change in conformation takes place , which causes signal transduction via G proteins (from the G i family ). As a result, adenylyl cyclase is inhibited. The metabotropic glutamate receptor 4 has disulfide bridges and is glycosylated .

The metabotropic glutamate receptor 4, like the metabotropic glutamate receptor 1 , is probably involved in the umami taste on the tongue.

Orthosteric ligands

  • Cinnabaric acid , a tryptophan metabolite
  • LSP1-2111: agonist
  • LSP4-2022: agonist

Positive Allosteric Modulators (PAM)

  • Foliglurax (PXT-002331, DT-1687)
  • Tricyclic thiazolopyrazole derivative 22a: EC 50 = 9 nM, E max = 120%
  • ML-128 : EC 50 = 240 nM, E max = 182%
  • VU-0418506
  • VU-001171: EC 50 = 650 nM, E max = 141%, 36-fold shift
  • VU-0155041: subtype-selective PAM, also works in vivo
  • PHCCC : negative allosteric modulator of mGluR4 and mGluR1, agonist of mGluR6

Individual evidence

  1. ↑ a b c GRM4 - Metabotropic glutamate receptor 4 precursor - Homo sapiens (Human) - GRM4 gene & protein. In: uniprot.org. September 12, 2018, accessed October 8, 2018 .
  2. ↑ K. Yasumatsu, T. Manabe, R. Yoshida, K. Iwatsuki, H. Uneyama, I. Takahashi, Y. Ninomiya: Involvement of multiple taste receptors in umami taste: analysis of gustatory nerve responses in metabotropic glutamate receptor 4 knockout mice . In: Journal of Physiology. Volume 593, No. 4, February 2015, pp. 1021-1034; doi: 10.1113 / jphysiol.2014.284703 , PMC 4398535 (free full text).
  3. ↑ X. Li et al.: Human receptors for sweet and umami taste. In: Proc. Natl. Acad. Sci. USA 99 (7), 2002, pp. 4692-4696. PMID 11917125 . (PDF) .
  4. ↑ 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 . In: Molecular Pharmacology . 81, No. 5, May 2012, pp. 643-56. doi : 10.1124 / mol.111.074765 . PMID 22311707 .
  5. ↑ 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 . In: Neuropharmacology . 59, No. 7-8, December 2010, pp. 627-34. doi : 10.1016 / j.neuropharm.2010.08.008 . PMID 20713068 .
  6. ↑ 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 . In: FASEB J. . 26, No. 4, 2012, pp. 1682-93. doi : 10.1096 / fj.11-195941 . PMID 22223752 .
  7. ↑ 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 . In: Journal of Medicinal Chemistry . 54, No. 14, July 2011, pp. 5070-81. doi : 10.1021 / jm200290z . PMID 21688779 .
  8. ↑ Hopkins CR, Niswender CM, Lewis LM, Weaver CD, Lindsley CW: Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator . In: Probe Reports from the NIH Molecular Libraries Program [Internet] . September. PMID 21433377 .
  9. ↑ 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) . In: Journal of Medicinal Chemistry . 52, No. 14, July 2009, pp. 4115-8. doi : 10.1021 / jm9005065 . PMID 19469556 . PMC 2765192 (free full text).
  10. ↑ 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: Development and Antiparkinsonian Activity of VU0418506 , a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2 / 4 Heteromers . In: ACS Chem Neurosci . 7, 2016, pp. 1201-11. doi : 10.1021 / acschemneuro.6b00036 . PMID 27441572 .
  11. ↑ 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) . In: ACS Chem Neurosci . 7, 2016, pp. 1192-200. doi : 10.1021 / acschemneuro.6b00035 . PMID 27075300 .
  12. ↑ 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 . In: Bioorganic & Medicinal Chemistry Letters . 19, No. 3, February 2009, pp. 962-6. doi : 10.1016 / j.bmcl.2008.11.104 . PMID 19097893 . PMC 3787871 (free full text).
  13. ↑ 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 . In: Molecular Pharmacology . 74, No. 5, November 2008, pp. 1345-58. doi : 10.1124 / mol.108.049551 . PMID 18664603 . PMC 2574552 (free full text).
  14. ^ Watkins JC, Jane DE: The glutamate story . In: British Journal of Pharmacology . 147 Suppl 1, January 2006, pp. S100-8. doi : 10.1038 / sj.bjp.0706444 . PMID 16402093 . PMC 1760733 (free full text).
  15. ↑ Beqollari D, Kammermeier PJ: The mGlu (4) receptor allosteric modulator N-phenyl-7- (hydroxyimino) cyclopropa [b] chromene-1a-carboxamide acts as a direct agonist at mGlu (6) receptors . In: European Journal of Pharmacology . 589, No. 1-3, July 2008, pp. 49-52. doi : 10.1016 / j.ejphar.2008.06.054 . PMID 18593581 .