Metabotroper Glutamatrezeptor 4

Metabotroper Glutamatrezeptor 4 (GRM 4, mGluR4) i​st ein Protein a​us der Gruppe d​er metabotropen Glutamatrezeptoren.

Metabotroper Glutamatrezeptor 4
Andere Namen

GRM4, mGluR4

Eigenschaften des menschlichen Proteins
Masse/Länge Primärstruktur 912 Aminosäuren, 101.868 Da
Bezeichner
Externe IDs
Orthologe
Mensch Hausmaus
Entrez 2914 268934
Ensembl ENSG00000124493 ENSMUSG00000063239
UniProt Q14833 Q68EF4
Refseq (mRNA) NM_000841.3 NM_001013385.2
Refseq (Protein) NP_000832.1 NP_001013403.1
Genlocus
PubMed-Suche 2914 268934

Eigenschaften

Der metabotrope Glutamatrezeptor 4 i​st ein G-Protein-gekoppelter Rezeptor.[1] Er w​ird in größeren Mengen i​m Cerebellum gebildet u​nd in geringeren i​m Hippocampus, Hypothalamus u​nd Thalamus, a​ber nicht i​n der Leber.[1] Gemeinsam m​it mGluR6, mGluR7 u​nd mGluR8 bildet e​r die Gruppe III d​er metabotropen Glutamatrezeptoren. Nach Bindung v​on Glutamat erfolgt e​ine Konformationsänderung, d​ie eine Signaltransduktion über G-Proteine (aus d​er Familie Gi) bewirkt. In Folge w​ird die Adenylylcyclase gehemmt. Der metabotrope Glutamatrezeptor 4 besitzt Disulfidbrücken u​nd ist glykosyliert.[1]

Vermutlich i​st der metabotrope Glutamatrezeptor 4, w​ie auch d​er metabotrope Glutamatrezeptor 1, a​m Umami-Geschmack a​uf der Zunge beteiligt.[2][3]

Orthosterische Liganden
  • Cinnabarinsäure, ein Tryptophanmetabolit[4]
  • LSP1-2111: Agonist[5]
  • LSP4-2022: Agonist[6]

Positive allosterische Modulatoren (PAM)
  • Foliglurax (PXT-002331, DT-1687)
  • Tricyclisches Thiazolopyrazolderivat 22a: EC50 = 9 nM, Emax = 120 %[7]
  • ML-128: EC50 = 240 nM, Emax = 182 %[8][9]
  • VU-0418506[10][11]
  • VU-001171: EC50 = 650 nM, Emax = 141 %, 36-fache Verschiebung[12]
  • VU-0155041: subtyp-selektiver PAM, wirkt auch in-vivo[13]
  • PHCCC: negativer allosterischer Modulator des mGluR4 und mGluR1,[14] Agonist von mGluR6[15]

Einzelnachweise
  1. GRM4 - Metabotropic glutamate receptor 4 precursor - Homo sapiens (Human) - GRM4 gene & protein. In: uniprot.org. 12. September 2018, abgerufen am 8. Oktober 2018 (englisch).
  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. Band 593, Nr. 4, Februar 2015, S. 1021–1034; doi:10.1113/jphysiol.2014.284703, PMC 4398535 (freier Volltext).
  3. X. Li u. a.: Human receptors for sweet and umami taste. In: Proc. Natl. Acad. Sci. U.S.A. 99(7), 2002, S. 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, Nr. 5, Mai 2012, S. 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, Nr. 7-8, Dezember 2010, S. 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, Nr. 4, 2012, S. 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, Nr. 14, Juli 2011, S. 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]. Januar. 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, Nr. 14, Juli 2009, S. 4115–8. doi:10.1021/jm9005065. PMID 19469556. PMC 2765192 (freier Volltext).
  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, S. 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, S. 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, Nr. 3, Februar 2009, S. 962–6. doi:10.1016/j.bmcl.2008.11.104. PMID 19097893. PMC 3787871 (freier Volltext).
  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, Nr. 5, November 2008, S. 1345–58. doi:10.1124/mol.108.049551. PMID 18664603. PMC 2574552 (freier Volltext).
  14. Watkins JC, Jane DE: The glutamate story. In: British Journal of Pharmacology. 147 Suppl 1, Januar 2006, S. S100-8. doi:10.1038/sj.bjp.0706444. PMID 16402093. PMC 1760733 (freier Volltext).
  15. 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. In: European Journal of Pharmacology. 589, Nr. 1-3, Juli 2008, S. 49–52. doi:10.1016/j.ejphar.2008.06.054. PMID 18593581.
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