Metabotropni glutamatni receptor 3

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Metabotropni glutamatni receptor 3
PDB prikaz baziran na 2e4u.
Dostupne strukture
3SM9
Identifikatori
Simboli	GRM3; GLUR3; GPRC1C; MGLUR3; mGlu3
Vanjski ID	OMIM: 601115 MGI: 1351340 HomoloGene: 651 IUPHAR: mGlu3 GeneCards: GRM3 Gene
Ontologija gena Molekularna funkcija • aktivnost grupe II metabotropnog glutamatnog receptora • aktivnost signalnog transducera • receptorska aktivnost • aktivnost G protein spregnutog receptora • aktivnost regulatora kalcijumovog kanala • aktivnost glutamatnog receptora Celularna komponenta • ćelijska membrana • integralno sa ćelijskom membranom • postsinaptička gustina • integralno sa membranom • akson • presinaptička membrana • dendritska osnova • postsinaptička membrana Biološki proces • Signalni put G protein spregnutog receptora • negativna regulacija aktivnosti adenilat ciklaze • inhibicija adenilat ciklazne aktivnosti signalnim putem G protein spregnutog glutamatnog receptora • sinaptička transmisija • regulacija sinaptičke transmisije
Pregled RNK izražavanja
podaci
Ortolozi
Vrsta	Čovek	Miš
Entrez	2913	108069
Ensembl	ENSG00000198822	ENSMUSG00000003974
UniProt	Q14832	Q9QYS2
RefSeq (mRNA)	NM_000840.2	NM_181850.2
RefSeq (protein)	NP_000831.2	NP_862898.1
Lokacija (UCSC)	Chr 7: 86.27 - 86.49 Mb	Chr 5: 9.49 - 9.73 Mb
PubMed pretraga	[1]	[2]

Metabotropni glutamatni receptor 3 je protein koji je kod ljudi kodiran GRM3 genom.^[1][2]

L-glutamat je jedan od glavnih ekscitatornih neurotransmitera centralnog nervnog sistema. On aktivira jonotropne i metabotropne glutamatne receptore. Glutamatergična neurotransmisija učestvuje u većini aspekata normalne moždane funkcije. Ona može da bude modifikovana mnogim neuropatološkim uslovima. Metabotropini glutamatni receptori su familija G protein spregnutih receptora, koji se dele u tri grupe na bazi homologije sekvenci, mehanizama prenosa signala, i farmakoloških svojstava. Grupa I obuhvata GRM1 i GRM5. Za njih je pokazano da aktiviraju fosfolipazu C. Grupa II obuhvata GRM2 i GRM3, dok su grupi III GRM4, GRM6, GRM7 i GRM8. Grupe II i III receptora su povezane sa inhibicijom kaskade cikličnog AMP-a, ali se razlikuju u selektivnost na agoniste.^[2]

Ligandi

Potpuno mGluR3 selektivni agensi nisu dostupni. Poznati su mešoviti mGluR2/3 (grupa II) ligandi sa selektivnošću u odnosu na druge mGluR podtipove. Neki od njih imaju nisku oralnu biodostupnost, ali postoji mogućnost njihove upotrebe u obliku proleka.^[3]

Agonisti

• sa biciklo[3.1.0]heksanskom osnovom
  • MGS-0028^[4]
  • LY404040^[5]
  • LY379268^[6]
  • LY354740^[7]; njegov (+)-C4α-metil analog je GluR2 agonist / GluR3 antagonist^[8]
• (R)-2-amino-4-(4-hidroksi[1,2,5]tiadiazol-3-il)buterna kiselina^[9]

Antagonist

• CECXG - 38 puta je selektivniji za mGlu₃ u odnosu na mGlu₂
• LY-341,495 i njegov 1-fluoro analog^[10]: potentni ortosterni antagonisti
• MGS-0039^[11], HYDIA^[12] (oba sa biciklo[3.1.0]heksanskom osnovom)

Alosterni modulatori

• MNI-137^[13]: inhibitor
• jedinjenje 7p^[14]: nekompetitivni antagonist

Interakcije

Metabotropni glutamatni receptor 3 formira interakcije sa GRIP1,^[15] PICK1^[15] i PPM1A.^[16]

Reference

1. Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC (Mar 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. 
2. „Entrez Gene: GRM3 glutamate receptor, metabotropic 3”. Entrez Gene: GRM3 glutamate receptor, metabotropic 3. 
3. Rorick-Kehn LM, Perkins EJ, Knitowski KM, et al. (2006). „Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344”. J. Pharmacol. Exp. Ther. 316 (2): 905–13. DOI:10.1124/jpet.105.091926. PMID 16223873. 
4. Nakazato A, Kumagai T, Sakagami K, et al. (2000). „Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists”. J. Med. Chem. 43 (25): 4893–909. DOI:10.1021/jm000346k. PMID 11123999. 
5. Monn JA, Massey SM, Valli MJ, et al. (2007). „Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors”. J. Med. Chem. 50 (2): 233–40. DOI:10.1021/jm060917u. PMID 17228865. 
6. Monn JA, Valli MJ, Massey SM, et al. (1999). „Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors”. J. Med. Chem. 42 (6): 1027–40. DOI:10.1021/jm980616n. PMID 10090786. 
7. Monn JA, Valli MJ, Massey SM, et al. (1997). „Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties”. J. Med. Chem. 40 (4): 528–37. DOI:10.1021/jm9606756. PMID 9046344. 
8. Dominguez C, Prieto L, Valli MJ, et al. (2005). „Methyl substitution of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate (LY354740) determines functional activity at metabotropic glutamate receptors: identification of a subtype selective mGlu2 receptor agonist”. J. Med. Chem. 48 (10): 3605–12. DOI:10.1021/jm040222y. PMID 15887967. 
9. Clausen RP, Bräuner-Osborne H, Greenwood JR, et al. (2002). „Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid”. J. Med. Chem. 45 (19): 4240–5. DOI:10.1021/jm020122x. PMID 12213064. 
10. Sakagami K, Yasuhara A, Chaki S, et al. (2008). „Synthesis, in vitro pharmacology, and pharmacokinetic profiles of 2-[1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid and its 6-heptyl ester, a potent mGluR2 antagonist”. Bioorg. Med. Chem. 16 (8): 4359–66. DOI:10.1016/j.bmc.2008.02.066. PMID 18348906. 
11. a) Nakazato A, Sakagami K, Yasuhara A, et al. (2004). „Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists”. J. Med. Chem. 47 (18): 4570–87. DOI:10.1021/jm0400294. PMID 15317467. ,
    b) Yasuhara A, Nakamura M, Sakagami K, et al. (2006). „Prodrugs of 3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039): a potent and orally active group II mGluR antagonist with antidepressant-like potential”. Bioorg. Med. Chem. 14 (12): 4193–207. DOI:10.1016/j.bmc.2006.01.060. PMID 16487713. ,
    c) Yasuhara A, Sakagami K, Yoshikawa R, Chaki S, Nakamura M, Nakazato A (2006). „Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists”. Bioorg. Med. Chem. 14 (10): 3405–20. DOI:10.1016/j.bmc.2005.12.061. PMID 16431115. 
12. Woltering TJ, Adam G, Huguenin P, et al. (2008). „Asymmetric synthesis and receptor pharmacology of the group II mGlu receptor ligand (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid-HYDIA”. ChemMedChem 3 (2): 323–35. DOI:10.1002/cmdc.200700226. PMID 18058780. 
13. Hemstapat K, Da Costa H, Nong Y, et al. (2007). „A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors”. J. Pharmacol. Exp. Ther. 322 (1): 254–64. DOI:10.1124/jpet.106.117093. PMID 17416742. 
14. Woltering TJ, Wichmann J, Goetschi E, et al. (2008). „Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 3. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists”. Bioorg. Med. Chem. Lett. 18 (8): 2725–9. DOI:10.1016/j.bmcl.2008.02.076. PMID 18374569. 
15. Hirbec, Hélène; Perestenko Olga, Nishimune Atsushi, Meyer Guido, Nakanishi Shigetada, Henley Jeremy M, Dev Kumlesh K (May 2002). „The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs”. J. Biol. Chem. (United States) 277 (18): 15221–4. DOI:10.1074/jbc.C200112200. ISSN 0021-9258. PMID 11891216. 
16. Flajolet, Marc; Rakhilin Sergey, Wang Hong, Starkova Natalia, Nuangchamnong Nina, Nairn Angus C, Greengard Paul (December 2003). „Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3”. Proc. Natl. Acad. Sci. U.S.A. (United States) 100 (26): 16006–11. DOI:10.1073/pnas.2136600100. ISSN 0027-8424. PMC 307683. PMID 14663150. 

Literatura

• Makoff A, Volpe F, Lelchuk R, et al. (1997). „Molecular characterization and localization of human metabotropic glutamate receptor type 3.”. Brain Res. Mol. Brain Res. 40 (1): 55–63. DOI:10.1016/0169-328X(96)00037-X. PMID 8840013. 
• Emile L, Mercken L, Apiou F, et al. (1997). „Molecular cloning, functional expression, pharmacological characterization and chromosomal localization of the human metabotropic glutamate receptor type 3.”. Neuropharmacology 35 (5): 523–30. DOI:10.1016/0028-3908(96)84622-3. PMID 8887960. 
• Corti C, Sala CF, Yang F, et al. (2001). „Genomic organization of the human metabotropic glutamate receptor subtype 3.”. J. Neurogenet. 14 (4): 207–25, 271. DOI:10.3109/01677060009084499. PMID 11342382. 
• Corti C, Xuereb JH, Corsi M, Ferraguti F (2001). „Identification and characterization of the promoter region of the GRM3 gene.”. Biochem. Biophys. Res. Commun. 286 (2): 381–7. DOI:10.1006/bbrc.2001.5391. PMID 11500049. 
• Tomiyama M, Kimura T, Maeda T, et al. (2001). „Expression of metabotropic glutamate receptor mRNAs in the human spinal cord: implications for selective vulnerability of spinal motor neurons in amyotrophic lateral sclerosis.”. J. Neurol. Sci. 189 (1-2): 65–9. DOI:10.1016/S0022-510X(01)00561-5. PMID 11535235. 
• Rosemond E, Peltekova V, Naples M, et al. (2002). „Molecular determinants of high affinity binding to group III metabotropic glutamate receptors.”. J. Biol. Chem. 277 (9): 7333–40. DOI:10.1074/jbc.M110476200. PMID 11744707. 
• Martí SB, Cichon S, Propping P, Nöthen M (2002). „Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population.”. Am. J. Med. Genet. 114 (1): 46–50. DOI:10.1002/ajmg.1624. PMID 11840505. 
• Kitano J, Kimura K, Yamazaki Y, et al. (2002). „Tamalin, a PDZ domain-containing protein, links a protein complex formation of group 1 metabotropic glutamate receptors and the guanine nucleotide exchange factor cytohesins.”. J. Neurosci. 22 (4): 1280–9. PMID 11850456. 
• Hirbec H, Perestenko O, Nishimune A, et al. (2002). „The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs.”. J. Biol. Chem. 277 (18): 15221–4. DOI:10.1074/jbc.C200112200. PMID 11891216. 
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). „Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.”. Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. DOI:10.1073/pnas.242603899. PMC 139241. PMID 12477932. 
• Scherer SW, Cheung J, MacDonald JR, et al. (2003). „Human chromosome 7: DNA sequence and biology.”. Science 300 (5620): 767–72. DOI:10.1126/science.1083423. PMC 2882961. PMID 12690205. 
• Fujii Y, Shibata H, Kikuta R, et al. (2004). „Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia.”. Psychiatr. Genet. 13 (2): 71–6. DOI:10.1097/01.ypg.0000056682.82896.b0. PMID 12782962. 
• Aronica E, Gorter JA, IJlst-Keizers H, et al. (2003). „Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins.”. Eur. J. Neurosci. 17 (10): 2106–18. DOI:10.1046/j.1460-9568.2003.02657.x. PMID 12786977. 
• Hillier LW, Fulton RS, Fulton LA, et al. (2003). „The DNA sequence of human chromosome 7.”. Nature 424 (6945): 157–64. DOI:10.1038/nature01782. PMID 12853948. 
• Flajolet M, Rakhilin S, Wang H, et al. (2004). „Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3.”. Proc. Natl. Acad. Sci. U.S.A. 100 (26): 16006–11. DOI:10.1073/pnas.2136600100. PMC 307683. PMID 14663150. 
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Povezano

• Metabotropni glutamatni receptor

Vanjske veze

• „Metabotropic Glutamate Receptors: mGlu₃”. Metabotropic Glutamate Receptors: mGlu₃. International Union of Basic and Clinical Pharmacology. Arhivirano iz originala na datum 2014-08-08.