Metabotropni glutamatni receptor 1

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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	Miš
Entrez	2911	14816
Ensembl	ENSG00000152822	ENSMUSG00000019828
UniProt	Q13255	P97772
RefSeq (mRNA)	NM_000838.3	NM_001114333.2
RefSeq (protein)	NP_000829.2	NP_001107805.1
Lokacija (UCSC)	Chr 6: 146.35 - 146.76 Mb	Chr 10: 10.41 - 10.8 Mb
PubMed pretraga	[1]	[2]

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. „Entrez Gene: GRM1 glutamate receptor, metabotropic 1”. 
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. 
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. 
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. 
5. 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. 
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. 

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. 
• Tu JC, Xiao B, Yuan JP, et al. (1998). „Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors.”. Neuron 21 (4): 717–26. DOI:10.1016/S0896-6273(00)80589-9. PMID 9808459. 
• 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. 
• Robbins MJ, Ciruela F, Rhodes A, McIlhinney RA (1999). „Characterization of the dimerization of metabotropic glutamate receptors using an N-terminal truncation of mGluR1alpha.”. J. Neurochem. 72 (6): 2539–47. DOI:10.1046/j.1471-4159.1999.0722539.x. PMID 10349865. 
• Mody N, Hermans E, Nahorski SR, Challiss RA (1999). „Inhibition of N-linked glycosylation of the human type 1alpha metabotropic glutamate receptor by tunicamycin: effects on cell-surface receptor expression and function.”. Neuropharmacology 38 (10): 1485–92. DOI:10.1016/S0028-3908(99)00099-4. PMID 10530810. 
• Francesconi A, Duvoisin RM (2000). „Opposing effects of protein kinase C and protein kinase A on metabotropic glutamate receptor signaling: selective desensitization of the inositol trisphosphate/Ca2+ pathway by phosphorylation of the receptor-G protein-coupling domain.”. Proc. Natl. Acad. Sci. U.S.A. 97 (11): 6185–90. DOI:10.1073/pnas.97.11.6185. PMC 18579. PMID 10823959. 
• Ganesh S, Amano K, Yamakawa K (2000). „Assignment of the gene GRM1 coding for metabotropic glutamate receptor 1 to human chromosome band 6q24 by in situ hybridization.”. Cytogenet. Cell Genet. 88 (3–4): 314–5. DOI:10.1159/000015517. PMID 10828618. 
• Ray K, Hauschild BC (2000). „Cys-140 is critical for metabotropic glutamate receptor-1 dimerization”. J. Biol. Chem. 275 (44): 34245–51. DOI:10.1074/jbc.M005581200. PMID 10945991. 
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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.