Metabotroper Glutamatrezeptor 5

Metabotropic glutamate receptor 5
Andere Namen	mGluR5
Eigenschaften des menschlichen Proteins
Masse/Länge Primärstruktur	1.212 Aminosäuren, 132.469 Da
Bezeichner
Externe IDs	GeneCards: GRM5; OMIM: 604102; UniProt P41594;
Vorkommen
Homologie-Familie	Hovergen
	Orthologe (Mensch)
Entrez	2915
Ensembl	ENSG00000168959
UniProt	P41594
Refseq (mRNA)	NM_000842.4
Refseq (Protein)	NP_000833.1
PubMed-Suche	2915

Metabotroper Glutamatrezeptor 5 (GRM 5, mGluR5) ist ein Protein aus der Gruppe der metabotropen Glutamatrezeptoren.

Eigenschaften

Der metabotrope Glutamatrezeptor 5 ist ein G-Protein-gekoppelter Rezeptor.^[1] Gemeinsam mit mGluR1 bildet er die Gruppe I der metabotropen Glutamatrezeptoren. Nach Bindung von Glutamat erfolgt eine Konformationsänderung, die eine Signaltransduktion über G-Proteine (aus der Familie G_q) bewirkt. In Folge wird die Phospholipase C aktiviert, was zur Anreicherung von IP₃ und Diacylglycerol (DAG) im Zellinneren führt. Über IP₃-Rezeptoren kommt es zur Freisetzung von Calcium ionen aus dem endoplasmatischen Retikulum, während DAG vor allem die Proteinkinase C aktiviert. Der metabotrope Glutamatrezeptor 5 besitzt Disulfidbrücken und ist glykosyliert, methyliert und phosphoryliert.^[1] Der metabotrope Glutamatrezeptor 5 ist an der synaptischen Plastizität beteiligt.^[1]

Liganden

Agonist

CHPG (2-amino-2-(2-chlor-5-hydroxyphenyl)essigsäure)

Antagonisten

Lithium^[2]
RO4917523 (Roche)^[3]
LY-344,545
Mavoglurant (Bezeichnung während der Entwicklungsphase: AFQ056) (Novartis)^[3]
Remeglurant
SIB-1893

Positive allosterische Modulatoren

ADX-47273^[4]
CPPHA^[5]^[6]
VU-29: K_i = 244 nM, EC₅₀ = 9,0 nM; VU-36: K_i = 95 nM, EC₅₀ = 10,6 nM^[7]
VU-1545: K_i = 156 nM, EC₅₀ = 9.6 nM^[8]
CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamid)^[9]
DFB (1-(3-fluorphenyl)-N-((3-fluorphenyl)methylidenamino)methanimin)

Orthosterischer Antagonist

LY-344,545

Negative allosterische Modulatoren

Einzelnachweise

↑ ^a ^b ^c UniProt GRM5 - Metabotropic glutamate receptor 5 precursor - Homo sapiens (Human) - GRM5 gene & protein. Abgerufen am 6. November 2018.
↑ David Amaral: Autism Spectrum Disorders. Oxford University Press, 2011, ISBN 978-0-19-970747-8, S. 806.
↑ ^a ^b Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease, 5th Edition, Academic Press, 2014, ISBN 978-0-12-410529-4
↑ Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G, Atkinson PJ, Popiolek M, Wantuch C, Khawaja X, Smith D, Olsen M, Kouranova E, Lai M, Pruthi F, Pulicicchio C, Day M, Gilbert A, Pausch MH, Brandon NJ, Beyer CE, Comery TA, Logue S, Rosenzweig-Lipson S, Marquis KL: ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. In: The Journal of Pharmacology and Experimental Therapeutics. 327. Jahrgang, Nr. 3, Dezember 2008, S. 827–39, doi:10.1124/jpet.108.136580, PMID 18753411.
↑ Zhao Z, Wisnoski DD, O’Brien JA, Lemaire W, Williams DL, Jacobson MA, Wittman M, Ha SN, Schaffhauser H, Sur C, Pettibone DJ, Duggan ME, Conn PJ, Hartman GD, Lindsley CW: Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA. In: Bioorganic & Medicinal Chemistry Letters. 17. Jahrgang, Nr. 5, März 2007, S. 1386–91, doi:10.1016/j.bmcl.2006.11.081, PMID 17210250.
↑ O’Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD, Lindsley CW, Schaffhauser HJ, Rowe B, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL: A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain. In: The Journal of Pharmacology and Experimental Therapeutics. 309. Jahrgang, Nr. 2, Mai 2004, S. 568–77, doi:10.1124/jpet.103.061747, PMID 14747613.
↑ Chen Y, Nong Y, Goudet C, Hemstapat K, de Paulis T, Pin JP, Conn PJ: Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses. In: Molecular Pharmacology. 71. Jahrgang, Nr. 5, Mai 2007, S. 1389–98, doi:10.1124/mol.106.032425, PMID 17303702.
↑ de Paulis T, Hemstapat K, Chen Y, Zhang Y, Saleh S, Alagille D, Baldwin RM, Tamagnan GD, Conn PJ: Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes. In: Journal of Medicinal Chemistry. 49. Jahrgang, Nr. 11, Juni 2006, S. 3332–44, doi:10.1021/jm051252j, PMID 16722652.
↑ Kinney GG, O’Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK, Chen TB, Wisnoski DD, Lindsley CW, Tiller PR, Smith S, Jacobson MA, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL: A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. In: The Journal of Pharmacology and Experimental Therapeutics. 313. Jahrgang, Nr. 1, April 2005, S. 199–206, doi:10.1124/jpet.104.079244, PMID 15608073.
↑ Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley JN: Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. In: Science Translational Medicine. 4. Jahrgang, Nr. 131, April 2012, S. 131ra51, doi:10.1126/scitranslmed.3003501, PMID 22539775, PMC 4904784 (freier Volltext).

[uniprot-41594-1] UniProt GRM5 - Metabotropic glutamate receptor 5 precursor - Homo sapiens (Human) - GRM5 gene & protein. Abgerufen am 6. November 2018.

[ASDs-2] David Amaral: Autism Spectrum Disorders. Oxford University Press, 2011, ISBN 978-0-19-970747-8, S. 806.

[Rosenberg-3] Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease, 5th Edition, Academic Press, 2014, ISBN 978-0-12-410529-4

[pmid18753411-4] Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G, Atkinson PJ, Popiolek M, Wantuch C, Khawaja X, Smith D, Olsen M, Kouranova E, Lai M, Pruthi F, Pulicicchio C, Day M, Gilbert A, Pausch MH, Brandon NJ, Beyer CE, Comery TA, Logue S, Rosenzweig-Lipson S, Marquis KL: ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. In: The Journal of Pharmacology and Experimental Therapeutics. 327. Jahrgang, Nr. 3, Dezember 2008, S. 827–39, doi:10.1124/jpet.108.136580, PMID 18753411.

[pmid17210250-5] Zhao Z, Wisnoski DD, O’Brien JA, Lemaire W, Williams DL, Jacobson MA, Wittman M, Ha SN, Schaffhauser H, Sur C, Pettibone DJ, Duggan ME, Conn PJ, Hartman GD, Lindsley CW: Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA. In: Bioorganic & Medicinal Chemistry Letters. 17. Jahrgang, Nr. 5, März 2007, S. 1386–91, doi:10.1016/j.bmcl.2006.11.081, PMID 17210250.

[pmid14747613-6] O’Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD, Lindsley CW, Schaffhauser HJ, Rowe B, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL: A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain. In: The Journal of Pharmacology and Experimental Therapeutics. 309. Jahrgang, Nr. 2, Mai 2004, S. 568–77, doi:10.1124/jpet.103.061747, PMID 14747613.

[pmid17303702-7] Chen Y, Nong Y, Goudet C, Hemstapat K, de Paulis T, Pin JP, Conn PJ: Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses. In: Molecular Pharmacology. 71. Jahrgang, Nr. 5, Mai 2007, S. 1389–98, doi:10.1124/mol.106.032425, PMID 17303702.

[pmid16722652-8] Paulis T, Hemstapat K, Chen Y, Zhang Y, Saleh S, Alagille D, Baldwin RM, Tamagnan GD, Conn PJ: Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes. In: Journal of Medicinal Chemistry. 49. Jahrgang, Nr. 11, Juni 2006, S. 3332–44, doi:10.1021/jm051252j, PMID 16722652.

[pmid15608073-9] Kinney GG, O’Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK, Chen TB, Wisnoski DD, Lindsley CW, Tiller PR, Smith S, Jacobson MA, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL: A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. In: The Journal of Pharmacology and Experimental Therapeutics. 313. Jahrgang, Nr. 1, April 2005, S. 199–206, doi:10.1124/jpet.104.079244, PMID 15608073.

[10] Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley JN: Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. In: Science Translational Medicine. 4. Jahrgang, Nr. 131, April 2012, S. 131ra51, doi:10.1126/scitranslmed.3003501, PMID 22539775, PMC 4904784 (freier Volltext).

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