Metabotroper Glutamatrezeptor 4 GRM 4 mGluR4 ist ein Protein aus der Gruppe der metabotropen Glutamatrezeptoren Andere N

Metabotroper Glutamatrezeptor 4
Andere Namen	GRM4, mGluR4
Eigenschaften des menschlichen Proteins
Masse/Länge Primärstruktur	912 Aminosäuren, 101.868 Da
Bezeichner
Externe IDs	GeneCards: GRM4; OMIM: 604100; UniProt: Q14833;
Vorkommen
Homologie-Familie	Hovergen
	Orthologe
Mensch	Hausmaus
	Genlocus

Metabotroper Glutamatrezeptor 4 (GRM 4, mGluR4) ist ein Protein aus der Gruppe der metabotropen Glutamatrezeptoren.

Eigenschaften Bearbeiten

Der metabotrope Glutamatrezeptor 4 ist ein G-Protein-gekoppelter Rezeptor. Er wird in größeren Mengen im Cerebellum gebildet und in geringeren im Hippocampus, Hypothalamus und Thalamus, aber nicht in der Leber. Gemeinsam mit mGluR6, mGluR7 und mGluR8 bildet er die Gruppe III der metabotropen Glutamatrezeptoren. Nach Bindung von Glutamat erfolgt eine Konformationsänderung, die eine Signaltransduktion über G-Proteine (aus der Familie G_i) bewirkt. In Folge wird die Adenylylcyclase gehemmt. Der metabotrope Glutamatrezeptor 4 besitzt Disulfidbrücken und ist glykosyliert.

Vermutlich ist der metabotrope Glutamatrezeptor 4, wie auch der metabotrope Glutamatrezeptor 1, am Umami-Geschmack auf der Zunge beteiligt.

Orthosterische Liganden Bearbeiten

Cinnabarinsäure, ein Tryptophanmetabolit
LSP1-2111: Agonist
LSP4-2022: Agonist

Positive allosterische Modulatoren (PAM) Bearbeiten

Foliglurax (PXT-002331, DT-1687)
Tricyclisches Thiazolopyrazolderivat 22a: EC₅₀ = 9 nM, E_max = 120 %
ML-128: EC₅₀ = 240 nM, E_max = 182 %
VU-0418506
VU-001171: EC₅₀ = 650 nM, E_max = 141 %, 36-fache Verschiebung
VU-0155041: subtyp-selektiver PAM, wirkt auch in-vivo
PHCCC: negativer allosterischer Modulator des mGluR4 und mGluR1, Agonist von mGluR6

Einzelnachweise Bearbeiten

↑ GRM4 - Metabotropic glutamate receptor 4 precursor - Homo sapiens (Human) - GRM4 gene & protein. In: uniprot.org. 12. September 2018, abgerufen am 8. Oktober 2018 (englisch).
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).
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).
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. Jahrgang, Nr. 5, Mai 2012, S. 643–56, doi:10.1124/mol.111.074765, PMID 22311707.
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. Jahrgang, Nr. 7-8, Dezember 2010, S. 627–34, doi:10.1016/j.neuropharm.2010.08.008, PMID 20713068.
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. Jahrgang, Nr. 4, 2012, S. 1682–93, doi:10.1096/fj.11-195941, PMID 22223752.
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. Jahrgang, Nr. 14, Juli 2011, S. 5070–81, doi:10.1021/jm200290z, PMID 21688779.
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]. PMID 21433377.
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. Jahrgang, Nr. 14, Juli 2009, S. 4115–8, doi:10.1021/jm9005065, PMID 19469556, PMC 2765192 (freier Volltext).
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. Jahrgang, 2016, S. 1201–11, doi:10.1021/acschemneuro.6b00036, PMID 27441572.
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. Jahrgang, 2016, S. 1192–200, doi:10.1021/acschemneuro.6b00035, PMID 27075300.
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. Jahrgang, Nr. 3, Februar 2009, S. 962–6, doi:10.1016/j.bmcl.2008.11.104, PMID 19097893, PMC 3787871 (freier Volltext).
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. Jahrgang, Nr. 5, November 2008, S. 1345–58, doi:10.1124/mol.108.049551, PMID 18664603, PMC 2574552 (freier Volltext).
Watkins JC, Jane DE: The glutamate story. In: British Journal of Pharmacology. 147 Suppl 1. Jahrgang, Januar 2006, S. S100–8, doi:10.1038/sj.bjp.0706444, PMID 16402093, PMC 1760733 (freier Volltext).
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. Jahrgang, Nr. 1-3, Juli 2008, S. 49–52, doi:10.1016/j.ejphar.2008.06.054, PMID 18593581.

[uniprot-14833-1] 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. Jahrgang, 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. Jahrgang, Nr. 7-8, Dezember 2010, S. 627–34, doi:10.1016/j.neuropharm.2010.08.008, PMID 20713068.

[pmid22223752-6] 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. Jahrgang, Nr. 4, 2012, S. 1682–93, doi:10.1096/fj.11-195941, PMID 22223752.

[pmid21688779-7] 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. Jahrgang, 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]. PMID 21433377.

[pmid19469556-9] 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. Jahrgang, Nr. 14, Juli 2009, S. 4115–8, doi:10.1021/jm9005065, PMID 19469556, PMC 2765192 (freier Volltext).

[pmid27441572-10] 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. Jahrgang, 2016, S. 1201–11, doi:10.1021/acschemneuro.6b00036, PMID 27441572.

[pmid27075300-11] 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. Jahrgang, 2016, S. 1192–200, doi:10.1021/acschemneuro.6b00035, PMID 27075300.

[pmid19097893-12] 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. Jahrgang, Nr. 3, Februar 2009, S. 962–6, doi:10.1016/j.bmcl.2008.11.104, PMID 19097893, PMC 3787871 (freier Volltext).

[pmid18664603-13] 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. Jahrgang, Nr. 5, November 2008, S. 1345–58, doi:10.1124/mol.108.049551, PMID 18664603, PMC 2574552 (freier Volltext).

[pmid16402093-14] Watkins JC, Jane DE: The glutamate story. In: British Journal of Pharmacology. 147 Suppl 1. Jahrgang, Januar 2006, S. S100–8, doi:10.1038/sj.bjp.0706444, PMID 16402093, PMC 1760733 (freier Volltext).

[pmid18593581-15] 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. Jahrgang, Nr. 1-3, Juli 2008, S. 49–52, doi:10.1016/j.ejphar.2008.06.054, PMID 18593581.