Metabotropni glutamatni receptor 1

Metabotropni glutamatni receptor 1
Metabotropni glutamatni receptor 1
	PDB prikaz baziran na 1ewk.
Dostupne strukture
	3KS9
Identifikatori
Simboli	GRM1; GPRC1A; GRM1A; MGLUR1; MGLUR1A; mGlu1
Vanjski ID	OMIM: 604473 MGI: 1351338 HomoloGene: 649 IUPHAR: mGlu1 GeneCards: GRM1 Gene
Ontologija gena
Molekularna funkcija	• aktivnost prenosnika signala; • receptorska aktivnost; • aktivnost G-protein spregnutog receptora; • aktivnost glutamatnog receptora; • vezivanje estrogenskog receptora;
Celularna komponenta	• nukleus; • mikrozom; • ćelijska membrana; • integralno sa ćelijskom membranom; • postsinaptička gustina; • akson; • presinaptička membrana; • dendritna osnova;
Biološki proces	• aktivacija MAPKK aktivnosti; • aktivacija MAPK aktivnosti; • signalni put G-protein spregnutog receptora; • sinaptička transmisija; • lokomotorno ponašanje; • kalcijumom posredovana signalizacija; • regulacija MAPK kascade; • regulacija senzorne percepcije bola; • regulacija sinaptičke transmisije, glutamatergička; • celularni respons na električni stimulus;
Pregled RNK izražavanja
	podaci
Ortolozi
Vrsta	Čovek
Entrez	2911
Ensembl	ENSG00000152822
UniProt	Q13255
RefSeq (mRNA)	NM_000838.3
RefSeq (protein)	NP_000829.2
Lokacija (UCSC)	Chr 6:; 146.35 - 146.76 Mb
PubMed pretraga	[1]

Metabotropni glutamatni receptor 1 (GRM1) je ljudski gen koji kodira mGluR1 protein.^[1]^[2]^[3]

Funkcija

L-glutamat je ekscitatorni neurotransmiter u centralnom nervom sistemu. On aktivira jonotropne i metabotropne glutamatne receptore. Glutamatergična neurotransmisija učestvuje u znatnom broju aspekata normalne moždane funkcije i može da bude poremećena u slučajevima mnogih neuropatoloških oboljenja. Metabotropni glutamatni receptori su familija G protein spregnutih receptora, koja se deli u tri grupe na osnovu sekventne homologije, mehanizma prenosa signala, i farmakoloških svojstava. Grupa I obuhvata GRM1 i GRM5. Za te receptore je pokazano da aktiviraju fosfolipazu C. U grupi II su GRM2 i GRM3, dok su u grupi III GRM4, GRM6, GRM7 i GRM8. Grupe II i III receptora su vezana za inhibiciju kaskade cikličnog AMP, ali se razlikuju u njihovoj specifičnosti za agoniste. Alternativno splajsne varijante GRM1 gena su opisane, ali odgovarajući proteini pune dužine nisu bili određeni.^[1]

Klinički značaj

Mutacije GRM1 gena mogu da doprinesu podložnosti na razvoj melanoma.^[4]

Ligandi

Pored ortosternog mesta vezivanja liganda gde se glutamat vezuje, postoje bar još dva alosterna mesta vezivanja na mGluR1 receptoru.^[5] Znatan broj potentnih i specifičnih alosternih liganda – predominantno antagonista/inhibitora je razvijen, mada ortosterni podtip-selektivni ligandi nisu poznati.

JNJ-16259685: visoko potentan, selektivan nekompetitivan antagonist^[6]
R-214,127 i [³H]-analog: selektivni alosterni inhibitor visokog afiniteta^[7]
YM-202,074: selektivni alosterni antagonist visokog afiniteta^[8]
YM-230,888: selektivni alosterni antagonist visokog afiniteta^[9]
YM-298,198 i [³H]-analog: selektivni nekompetitivni antagonist^[10]
FTIDC: selektivni alosterni antagonist/inverzni agonist visokog afiniteta^[11]
A-841,720: potentan nekompetitivni antagonist; manje hmGluR5 vezivanje^[12]
VU-71: potencijator^[5]
Fluorisani oksazol-2-il-amidi 9H-ksanten-9-karboksilne kiseline: oralno dostupni potencijatori^[13]

Hemijska strukture mGluR1 selektivnih liganda.

Reference

^ ^а ^б „Entrez Gene: GRM1 glutamate receptor, metabotropic 1”.
^ Stephan D, Bon C, Holzwarth JA, Galvan M, Pruss RM (1996). „Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants”. Neuropharmacology. 35 (12): 1649—60. PMID 9076744. doi:10.1016/S0028-3908(96)00108-6.
^ Makoff AJ, Phillips T, Pilling C, Emson P (1997). „Expression of a novel splice variant of human mGluR1 in the cerebellum”. Neuroreport. 8 (13): 2943—7. PMID 9376535. doi:10.1097/00001756-199709080-00027.
^ Ortiz P, Vanaclocha F, López-Bran E, Esquivias JI, López-Estebaranz JL, Martín-González M, Arrue I, García-Romero D, Ochoa C, González-Perez A, Ruiz A, Real LM (2007). „Genetic analysis of the GRM1 gene in human melanoma susceptibility”. Eur. J. Hum. Genet. 15 (11): 1176—82. PMID 17609672. doi:10.1038/sj.ejhg.5201887.
^ ^а ^б Hemstapat, K.; de Paulis T; Chen, Y.; et al. (2006). „A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators”. Mol. Pharmacol. 70 (2): 616—26. PMID 16645124. doi:10.1124/mol.105.021857.
^ Lavreysen, H.; R, Wouters; Bischoff, F.; et al. (2004). „JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist”. Neuropharmacology. 47 (7): 961—72. PMID 15555631. doi:10.1016/j.neuropharm.2004.08.007.
^ Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, Lesage AS (2003). „[3H]R214127: a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists”. Mol. Pharmacol. 63 (5): 1082—93. PMID 12695537. doi:10.1124/mol.63.5.1082.
^ Kohara, A.; M, Takahashi; Yatsugi, S.; et al. (2008). „Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models”. Brain Res. 1191: 168—79. PMID 18164695. doi:10.1016/j.brainres.2007.11.035.
^ Kohara, A.; Y, Nagakura; Kiso, T.; et al. (2007). „Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models”. Eur. J. Pharmacol. 571 (1): 8—16. PMID 17597604. doi:10.1016/j.ejphar.2007.05.030.
^ Kohara, A.; T, Toya; Tamura, S.; et al. (2005). „Radioligand binding properties and pharmacological characterization of 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198), a high-affinity, selective, and noncompetitive antagonist of metabotropic glutamate receptor type 1”. J. Pharmacol. Exp. Ther. 315 (1): 163—9. PMID 15976016. doi:10.1124/jpet.105.087171.
^ Suzuki, G.; T, Kimura; Satow, A.; et al. (2007). „Pharmacological characterization of a new, orally active and potent allosteric metabotropic glutamate receptor 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)”. J. Pharmacol. Exp. Ther. 321 (3): 1144—53. PMID 17360958. doi:10.1124/jpet.106.116574.
^ El-Kouhen O; Lehto, S. G.; Pan, J. B.; et al. (2006). „Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist”. Br. J. Pharmacol. 149 (6): 761—74. PMC 2014656  . PMID 17016515. doi:10.1038/sj.bjp.0706877.
^ Vieira E, Huwyler J, Jolidon S, Knoflach F, Mutel V, Wichmann J (2009). „Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides as potent, orally available mGlu1 receptor enhancers”. Bioorg. Med. Chem. Lett. 19 (6): 1666—9. PMID 19233648. doi:10.1016/j.bmcl.2009.01.108.

Literatura

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Scherer, S. W.; Duvoisin, R. M.; Kuhn, R.; et al. (1997). „Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q.”. Genomics. 31 (2): 230—3. PMID 8824806. doi:10.1006/geno.1996.0036.
Brakeman, P. R.; Lanahan, A. A.; O'Brien R; et al. (1997). „Homer: a protein that selectively binds metabotropic glutamate receptors.”. Nature. 386 (6622): 284—8. PMID 9069287. doi:10.1038/386284a0.
Stephan, D.; C, Bon; Holzwarth, J. A.; et al. (1997). „Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants.”. Neuropharmacology. 35 (12): 1649—60. PMID 9076744. doi:10.1016/S0028-3908(96)00108-6.
Makoff AJ, Phillips T, Pilling C, Emson P (1997). „Expression of a novel splice variant of human mGluR1 in the cerebellum.”. Neuroreport. 8 (13): 2943—7. PMID 9376535. doi:10.1097/00001756-199709080-00027.
Francesconi A, Duvoisin RM (1998). „Role of the second and third intracellular loops of metabotropic glutamate receptors in mediating dual signal transduction activation.”. J. Biol. Chem. 273 (10): 5615—24. PMID 9488690. doi:10.1074/jbc.273.10.5615.
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Snow, B. E.; Hall, R. A.; Krumins, A. M.; et al. (1998). „GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain.”. J. Biol. Chem. 273 (28): 17749—55. PMID 9651375. doi:10.1074/jbc.273.28.17749.
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Vidi još

Metabotropni glutamatni receptor

Spoljašnje veze

„Metabotropic Glutamate Receptors: mGlu₁”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Архивирано из оригинала 03. 03. 2016. г.

[entrez-1] а ^б „Entrez Gene: GRM1 glutamate receptor, metabotropic 1”.

[pmid9076744-2] Stephan D, Bon C, Holzwarth JA, Galvan M, Pruss RM (1996). „Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants”. Neuropharmacology. 35 (12): 1649—60. PMID 9076744. doi:10.1016/S0028-3908(96)00108-6.

[pmid9376535-3] Makoff AJ, Phillips T, Pilling C, Emson P (1997). „Expression of a novel splice variant of human mGluR1 in the cerebellum”. Neuroreport. 8 (13): 2943—7. PMID 9376535. doi:10.1097/00001756-199709080-00027.

[pmid17609672-4] Ortiz P, Vanaclocha F, López-Bran E, Esquivias JI, López-Estebaranz JL, Martín-González M, Arrue I, García-Romero D, Ochoa C, González-Perez A, Ruiz A, Real LM (2007). „Genetic analysis of the GRM1 gene in human melanoma susceptibility”. Eur. J. Hum. Genet. 15 (11): 1176—82. PMID 17609672. doi:10.1038/sj.ejhg.5201887.

[Hemstapat_K,_de_Paulis_T,_Chen_Y,_et_al._2006_616–26-5] а ^б Hemstapat, K.; de Paulis T; Chen, Y.; et al. (2006). „A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators”. Mol. Pharmacol. 70 (2): 616—26. PMID 16645124. doi:10.1124/mol.105.021857.

[6] Lavreysen, H.; R, Wouters; Bischoff, F.; et al. (2004). „JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist”. Neuropharmacology. 47 (7): 961—72. PMID 15555631. doi:10.1016/j.neuropharm.2004.08.007.

[7] Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, Lesage AS (2003). „[3H]R214127: a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists”. Mol. Pharmacol. 63 (5): 1082—93. PMID 12695537. doi:10.1124/mol.63.5.1082.

[8] Kohara, A.; M, Takahashi; Yatsugi, S.; et al. (2008). „Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models”. Brain Res. 1191: 168—79. PMID 18164695. doi:10.1016/j.brainres.2007.11.035.

[9] Kohara, A.; Y, Nagakura; Kiso, T.; et al. (2007). „Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models”. Eur. J. Pharmacol. 571 (1): 8—16. PMID 17597604. doi:10.1016/j.ejphar.2007.05.030.

[10] Kohara, A.; T, Toya; Tamura, S.; et al. (2005). „Radioligand binding properties and pharmacological characterization of 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198), a high-affinity, selective, and noncompetitive antagonist of metabotropic glutamate receptor type 1”. J. Pharmacol. Exp. Ther. 315 (1): 163—9. PMID 15976016. doi:10.1124/jpet.105.087171.

[11] Suzuki, G.; T, Kimura; Satow, A.; et al. (2007). „Pharmacological characterization of a new, orally active and potent allosteric metabotropic glutamate receptor 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)”. J. Pharmacol. Exp. Ther. 321 (3): 1144—53. PMID 17360958. doi:10.1124/jpet.106.116574.

[12] El-Kouhen O; Lehto, S. G.; Pan, J. B.; et al. (2006). „Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist”. Br. J. Pharmacol. 149 (6): 761—74. PMC 2014656  . PMID 17016515. doi:10.1038/sj.bjp.0706877.

[pmid19233648-13] Vieira E, Huwyler J, Jolidon S, Knoflach F, Mutel V, Wichmann J (2009). „Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides as potent, orally available mGlu1 receptor enhancers”. Bioorg. Med. Chem. Lett. 19 (6): 1666—9. PMID 19233648. doi:10.1016/j.bmcl.2009.01.108.

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