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 OMIM604473 MGI1351338 HomoloGene649 IUPHAR: mGlu1 GeneCards: GRM1 Gene
Pregled RNK izražavanja
PBB GE GRM1 207299 s at tn.png
PBB GE GRM1 210939 s at tn.png
PBB GE GRM1 210940 s at tn.png
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[uredi - уреди]

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[uredi - уреди]

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

Ligandi[uredi - уреди]

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[uredi - уреди]

  1. 1.0 1.1 "Entrez Gene: GRM1 glutamate receptor, metabotropic 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2911. 
  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. 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). "[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. doi:10.1124/mol.63.5.1082. PMID 12695537. 
  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. 

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