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

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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

↑ ^1,0 ^1,1 „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. DOI:10.1016/S0028-3908(96)00108-6. PMID 9076744.
↑ Makoff AJ, Phillips T, Pilling C, Emson P (September 1997). „Expression of a novel splice variant of human mGluR1 in the cerebellum”. Neuroreport 8 (13): 2943–7. DOI:10.1097/00001756-199709080-00027. PMID 9376535.
↑ 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 (November 2007). „Genetic analysis of the GRM1 gene in human melanoma susceptibility”. Eur. J. Hum. Genet. 15 (11): 1176–82. DOI:10.1038/sj.ejhg.5201887. PMID 17609672.
↑ ^5,0 ^5,1 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. DOI:10.1124/mol.105.021857. PMID 16645124.
↑ Lavreysen H, Wouters R, Bischoff F, et al. (2004). „JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist”. Neuropharmacology 47 (7): 961–72. DOI:10.1016/j.neuropharm.2004.08.007. PMID 15555631.
↑ Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, Lesage AS (2003). „[3HR214127: 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. DOI:10.1124/mol.63.5.1082. PMID 12695537. ^{[mrtav link]}
↑ Kohara A, Takahashi M, 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. DOI:10.1016/j.brainres.2007.11.035. PMID 18164695.
↑ Kohara A, Nagakura Y, 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. DOI:10.1016/j.ejphar.2007.05.030. PMID 17597604.
↑ Kohara A, Toya T, 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. DOI:10.1124/jpet.105.087171. PMID 15976016.
↑ Suzuki G, Kimura T, 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. DOI:10.1124/jpet.106.116574. PMID 17360958.
↑ El-Kouhen O, Lehto SG, Pan JB, 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. DOI:10.1038/sj.bjp.0706877. PMC 2014656. PMID 17016515.
↑ 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. DOI:10.1016/j.bmcl.2009.01.108. PMID 19233648.

Literatura

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Desai MA, Burnett JP, Mayne NG, Schoepp DD (1995). „Cloning and expression of a human metabotropic glutamate receptor 1 alpha: enhanced coupling on co-transfection with a glutamate transporter.”. Mol. Pharmacol. 48 (4): 648–57. PMID 7476890.
Scherer SW, Duvoisin RM, Kuhn R, et al. (1997). „Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q.”. Genomics 31 (2): 230–3. DOI:10.1006/geno.1996.0036. PMID 8824806.
Brakeman PR, Lanahan AA, O'Brien R, et al. (1997). „Homer: a protein that selectively binds metabotropic glutamate receptors.”. Nature 386 (6622): 284–8. DOI:10.1038/386284a0. PMID 9069287.
Stephan D, Bon C, Holzwarth JA, et al. (1997). „Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants.”. Neuropharmacology 35 (12): 1649–60. DOI:10.1016/S0028-3908(96)00108-6. PMID 9076744.
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. DOI:10.1097/00001756-199709080-00027. PMID 9376535.
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. DOI:10.1074/jbc.273.10.5615. PMID 9488690.
Okamoto T, Sekiyama N, Otsu M, et al. (1998). „Expression and purification of the extracellular ligand binding region of metabotropic glutamate receptor subtype 1.”. J. Biol. Chem. 273 (21): 13089–96. DOI:10.1074/jbc.273.21.13089. PMID 9582347.
Snow BE, Hall RA, Krumins AM, 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. DOI:10.1074/jbc.273.28.17749. PMID 9651375.
Xiao B, Tu JC, Petralia RS, et al. (1998). „Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins.”. Neuron 21 (4): 707–16. DOI:10.1016/S0896-6273(00)80588-7. PMID 9808458.
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Ciruela F, Robbins MJ, Willis AC, McIlhinney RA (1999). „Interactions of the C terminus of metabotropic glutamate receptor type 1alpha with rat brain proteins: evidence for a direct interaction with tubulin.”. J. Neurochem. 72 (1): 346–54. DOI:10.1046/j.1471-4159.1999.0720346.x. PMID 9886087.
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Povezano

Metabotropni glutamatni receptor

Spoljašnje veze

„Metabotropic Glutamate Receptors: mGlu₁”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Arhivirano iz originala na datum 2016-03-03.

[entrez-1] 1,0 ^1,1 „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. DOI:10.1016/S0028-3908(96)00108-6. PMID 9076744.

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

[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 (November 2007). „Genetic analysis of the GRM1 gene in human melanoma susceptibility”. Eur. J. Hum. Genet. 15 (11): 1176–82. DOI:10.1038/sj.ejhg.5201887. PMID 17609672.

[Hemstapat_K,_de_Paulis_T,_Chen_Y,_et_al._2006_616–26-5] 5,0 ^5,1 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. DOI:10.1124/mol.105.021857. PMID 16645124.

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

[7] Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, Lesage AS (2003). „[3HR214127: 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. DOI:10.1124/mol.63.5.1082. PMID 12695537. ^{[mrtav link]}

[8] Kohara A, Takahashi M, 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. DOI:10.1016/j.brainres.2007.11.035. PMID 18164695.

[9] Kohara A, Nagakura Y, 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. DOI:10.1016/j.ejphar.2007.05.030. PMID 17597604.

[10] Kohara A, Toya T, 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. DOI:10.1124/jpet.105.087171. PMID 15976016.

[11] Suzuki G, Kimura T, 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. DOI:10.1124/jpet.106.116574. PMID 17360958.

[12] El-Kouhen O, Lehto SG, Pan JB, 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. DOI:10.1038/sj.bjp.0706877. PMC 2014656. PMID 17016515.

[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. DOI:10.1016/j.bmcl.2009.01.108. PMID 19233648.

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