Metabotropni glutamatni receptor 5
Glutamatni receptor, metabotropni 5 | |||||||||||
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Dostupne strukture | |||||||||||
3LMK | |||||||||||
Identifikatori | |||||||||||
Simboli | GRM5; GPRC1E; MGLUR5; mGlu5 | ||||||||||
Vanjski ID | OMIM: 604102 MGI: 1351342 HomoloGene: 37354 IUPHAR: mGlu5 GeneCards: GRM5 Gene | ||||||||||
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Pregled RNK izražavanja | |||||||||||
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podaci | |||||||||||
Ortolozi | |||||||||||
Vrsta | Čovek | Miš | |||||||||
Entrez | 2915 | 108071 | |||||||||
Ensembl | ENSG00000168959 | ENSMUSG00000049583 | |||||||||
UniProt | P41594 | Q3UVX5 | |||||||||
RefSeq (mRNA) | NM_000842.3 | NM_001033224.1 | |||||||||
RefSeq (protein) | NP_000833.1 | NP_001074883.1 | |||||||||
Lokacija (UCSC) | Chr 11: 88.24 - 88.8 Mb | Chr 7: 94.75 - 95.28 Mb | |||||||||
PubMed pretraga | [1] | [2] |
Metabotropni glutamatni receptor 5 je protein koji je kod ljudi kodiran GRM5 genom.[1][2]
Funkcija
Aminokiselina L-glutamat je glavni ekscitatorni neurotransmiter u centralnom nervnom sistemu koji aktivira jonotropne i metabotropne glutamatne receptore. Glutamatergična neurotransmisija učestvuje u većini aspekata normalnih moždanih funkcija. Ona može da bude poremećena u mnogim neuropatološkim oboljenjima. Metabotropni glutamatni receptori su familija G protein spregnutih receptora, koja se deli u tri grupe na osnovu homologije sekvence, mehanizma prenosa signala, i farmakoloških svojstava. Grupa I obuhvata GRM1 i GRM5. Ovi receptori aktiviraju fosfolipazu C. Grupa II obuhvata GRM2 i GRM3, dok su u grupi III GRM4, GRM6, GRM7, i GRM8. Receptori grupe II i III su vezani za inhibiciju kaskade cikličnog AMP-a ali se razlikuju u njihovim selektivnostima za agoniste. Alternativne splajsne varijante GRM8 su poznate, ali njihova svojstava nisu potpuno određena.[2]
Ligandi
Osim ortosternog mesta (mesta gde se endogeni ligand, glutamat, vezuje) najmanje dva različita alosterna mesta vezivanja postoje na mGluR5 receptoru.[3] Znatan broj potentnih i selektivnih mGluR5 liganda je razvijen.[4] Selektivni antagonisti i negativni alosterni modulatori mGluR5 receptora su oblast od posebnog interesa za farmaceutska istraživanja, usled njihove demonstrirane anksiolitičkie, antidepresivne i antizavisničke[5][6][7] uloge u životinjskim studijama i njihovog relativno benignog bezbednostnog profila.[8][9] mGluR5 receptori su isto tako izraženi izvan centralnog nervnog sistema, i za mGluR5 antagoniste je pokazano da su hepatoprotektivni i da mogu da budu korisni u tretmanu inflamacije i neuropatičkog bola.[10][11] Klinička upotreba ovih lekova može da bude ograničena usled nuspojava kao što su amnezija i psihotomimetički simptomi,[12][13][14][15] mada one mogu da bude prednost za pojedine indikacije.[16] mGluR5 pozitivni modulatori mogu da imaju nootropne efekte.[17]
Agonist
- CHPG (2-amino-2-(2-hloro-5-hidroksifenil)sirćetna kiselina)
Antagonist
Pozitivni alosterni modulatori
- ADX-47273[18]
- CPPHA[19][20]
- VU-29: Ki = 244 nM, EC50 = 9.0 nM; VU-36: Ki = 95 nM, EC50 = 10.6 nM[21]
- VU-1545: Ki = 156 nM, EC50 = 9.6 nM[22]
- CDPPB (3-cijano-N-(1,3-difenil-1H-pirazol-5-il)benzamid)[23]
- DFB (1-(3-fluorofenil)-N-((3-fluorofenil)metilideneamino)metanimin)
Ortosterni antagonist
Negativni alosterni modulatori
mGluR5 i adikcija
Miševi bez mGluR5 gena pokazuju nedostatak kokainske samoadministracije nezavisno od doze.[25] Iz toga proizilazi da ovaj receptor učestvuje u svojstvu nagrađivanja kokainom. Međutim, kasnije studije su pokazale da mGluR5 nokaut miševi delimično odgovaraju na kokain.[26]
Vidi još
Reference
- ^ Minakami R, Katsuki F, Yamamoto T, Nakamura K, Sugiyama H (1994). „Molecular cloning and the functional expression of two isoforms of human metabotropic glutamate receptor subtype 5”. Biochem Biophys Res Commun. 199 (3): 1136—43. PMID 7908515. doi:10.1006/bbrc.1994.1349.
- ^ а б „Entrez Gene: GRM5 glutamate receptor, metabotropic 5”.
- ^ Chen Y, Goudet C, Pin JP, Conn PJ (2008). „N4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors”. Mol. Pharmacol. 73 (3): 909—18. PMID 18056795. doi:10.1124/mol.107.040097.
- ^ Watkins JC, Jane DE. The glutamate story. British Journal of Pharmacology. 2006 Jan;147 Suppl 1:S100-8. . PMID 16402093. doi:10.1038/sj.bjp.0706444. Недостаје или је празан параметар
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(помоћ) - ^ Gass JT, Osborne MP, Watson NL, Brown JL, Olive MF (2009). „mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats”. Neuropsychopharmacology. 34 (4): 820—33. PMC 2669746
. PMID 18800068. doi:10.1038/npp.2008.140.
- ^ Bäckström P, Hyytiä P (2006). „Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking”. Neuropsychopharmacology. 31 (4): 778—86. PMID 16123768. doi:10.1038/sj.npp.1300845.
- ^ Bespalov, AY; Dravolina, OA; Sukhanov, I.; et al. (2005). „Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats”. Neuropharmacology. 49 Suppl 1: 167—78. PMID 16023685. doi:10.1016/j.neuropharm.2005.06.007.
- ^ Slassi A, Isaac M, Edwards L, Minidis A, Wensbo D, Mattsson J, Nilsson K, Raboisson P, McLeod D, Stormann TM, Hammerland LG, Johnson E (2005). „Recent advances in non-competitive mGlu5 receptor antagonists and their potential therapeutic applications”. Current Topics in Medicinal Chemistry. 5 (9): 897—911. PMID 16178734. CS1 одржавање: Вишеструка имена: списак аутора (веза)
- ^ Gasparini F, Bilbe G, Gomez-Mancilla B, Spooren W. mGluR5 antagonists: discovery, characterization and drug development. Current Opinion in Drug Discovery and Development. 11 (5): 655—65. септембар 2008. PMID 18729017. Недостаје или је празан параметар
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(помоћ)CS1 одржавање: Формат датума (веза) - ^ Hu Y, Dong L, Sun B, Guillon MA, Burbach LR, Nunn PA, Liu X, Vilenski O, Ford AP, Zhong Y, Rong W (јануар 2009). „The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception”. Neuroscience Letters. 450 (1): 12—7. PMID 19027050. CS1 одржавање: Вишеструка имена: списак аутора (веза)CS1 одржавање: Формат датума (веза)
- ^ Jesse, C. R.; Wilhelm EA; Bortolatto, C. F.; Savegnago, L.; Nogueira, C. W. (јануар 2009). „Selective blockade of mGlu5 metabotropic glutamate receptors is hepatoprotective against fulminant hepatic failure induced by lipopolysaccharide and d-galactosamine in mice”. Journal of Applied Toxicology. PMID 19153979. CS1 одржавање: Формат датума (веза)
- ^ Simonyi, A.; Schachtman, T. R.; Christoffersen, G. R. (2005 Jul-Aug). „The role of metabotropic glutamate receptor 5 in learning and memory processes”. Drug News and Perspectives. 18 (6): 353—61. PMID 16247513. Проверите вредност парамет(а)ра за датум:
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(помоћ) - ^ Manahan-Vaughan D, Braunewell KH (новембар 2005). „The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity”. Cerebral Cortex. 15 (11): 1703—13. PMID 15703249. CS1 одржавање: Формат датума (веза)
- ^ Palucha, A.; Pilc, A. (јул 2007). „Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs”. Pharmacology and Therapeutics. 115 (1): 116—47. PMID 17582504. CS1 одржавање: Формат датума (веза)
- ^ Christoffersen GR, Simonyi A, Schachtman TR, Clausen B, Clement D, Bjerre VK, Mark LT, Reinholdt M, Schmith-Rasmussen K, Zink LV. mGlu5 antagonism impairs exploration and memory of spatial and non-spatial stimuli in rats. Behavioural Brain Research. 191 (2): 235—45. август 2008. PMID 18471908. Недостаје или је празан параметар
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(помоћ)CS1 одржавање: Формат датума (веза) - ^ Xu J, Zhu Y, Contractor A, Heinemann SF. mGluR5 has a critical role in inhibitory learning. Journal of Neuroscience. 29 (12): 3676—84. март 2009. PMID 19321764. Недостаје или је празан параметар
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(помоћ)CS1 одржавање: Формат датума (веза) - ^ Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN, Watson NL, Xiang Z, Zhang Y, Jones PJ, Lindsley CW, Olive MF, Conn PJ. mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning. Neuropsychopharmacology. 2009 Mar 18. PMID 19295507
- ^ Liu, F.; Grauer, S.; Kelley, C.; et al. (2008). „ADX47273 [S-(4-fluoro-phenyl)3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-ylmethanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities”. J. Pharmacol. Exp. Ther. 327 (3): 827—39. PMID 18753411. doi:10.1124/jpet.108.136580.
- ^ Zhao, Z.; Wisnoski, DD; O'Brien, J. A.; et al. (2007). „Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA”. Bioorg. Med. Chem. Lett. 17 (5): 1386—91. PMID 17210250. doi:10.1016/j.bmcl.2006.11.081.
- ^ O'Brien, J. A.; Lemaire, W.; Wittmann, M.; et al. (2004). „A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain”. J. Pharmacol. Exp. Ther. 309 (2): 568—77. PMID 14747613. doi:10.1124/jpet.103.061747.
- ^ Chen, Y.; Nong, Y.; Goudet, C.; et al. (2007). „Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses”. Mol. Pharmacol. 71 (5): 1389—98. PMID 17303702. doi:10.1124/mol.106.032425.
- ^ de Paulis T; Hemstapat, K.; Chen, Y.; et al. (2006). „Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes”. J. Med. Chem. 49 (11): 3332—44. PMID 16722652. doi:10.1021/jm051252j.
- ^ Kinney, GG; O'Brien, J. A.; Lemaire, W.; et al. (2005). „A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models”. J. Pharmacol. Exp. Ther. 313 (1): 199—206. PMID 15608073. doi:10.1124/jpet.104.079244.
- ^ Silverman, J. L.; et al. (2012). „Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism”. Science Translational Medicine. 4 (131): 131ra51. doi:10.1126/scitranslmed.3003501.
- ^ Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F (2001). „Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice”. Nat. Neurosci. 4 (9): 873—4. PMID 11528416. doi:10.1038/nn0901-873.
- ^ Fowler MA, Varnell AL, Cooper DC (2011). „mGluR5 knockout mice exhibit normal conditioned place-preference to cocaine”. Nature Precedings.
Literatura
- Minakami R, Katsuki F, Sugiyama H (1993). „A variant of metabotropic glutamate receptor subtype 5: an evolutionally conserved insertion with no termination codon.”. Biochem. Biophys. Res. Commun. 194 (2): 622—7. PMID 7688218. doi:10.1006/bbrc.1993.1866.
- Daggett, LP; Sacaan, AI; Akong, M.; et al. (1996). „Molecular and functional characterization of recombinant human metabotropic glutamate receptor subtype 5.”. Neuropharmacology. 34 (8): 871—86. PMID 8532169. doi:10.1016/0028-3908(95)00085-K.
- Brakeman, PR; Lanahan, AA; 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.
- Minakami R, Jinnai N, Sugiyama H (1997). „Phosphorylation and calmodulin binding of the metabotropic glutamate receptor subtype 5 (mGluR5) are antagonistic in vitro.”. J. Biol. Chem. 272 (32): 20291—8. PMID 9242710. doi:10.1074/jbc.272.32.20291.
- 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. PMID 9651375. doi:10.1074/jbc.273.28.17749.
- 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. PMID 9808458. doi:10.1016/S0896-6273(00)80588-7.
- Enz R (2002). „The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7.”. FEBS Lett. 514 (2–3): 184—8. PMID 11943148. doi:10.1016/S0014-5793(02)02361-X.
- Saugstad, JA; Yang, S.; Pohl, J.; et al. (2002). „Interaction between metabotropic glutamate receptor 7 and alpha tubulin”. J. Neurochem. 80 (6): 980—8. PMC 2925652
. PMID 11953448. doi:10.1046/j.0022-3042.2002.00778.x.
- Nash, MS; Schell, MJ; Atkinson, PJ; et al. (2002). „Determinants of metabotropic glutamate receptor-5-mediated Ca2+ and inositol 1,4,5-trisphosphate oscillation frequency. Receptor density versus agonist concentration”. J. Biol. Chem. 277 (39): 35947—60. PMID 12119301. doi:10.1074/jbc.M205622200.
- Bates, B.; Xie, Y.; Taylor, N.; et al. (2003). „Characterization of mGluR5R, a novel, metabotropic glutamate receptor 5-related gene”. Brain Res. Mol. Brain Res. 109 (1–2): 18—33. PMID 12531512. doi:10.1016/S0169-328X(02)00458-8.
- Malherbe, P.; Kew, JN; Richards, JG; et al. (2003). „Identification and characterization of a novel splice variant of the metabotropic glutamate receptor 5 gene in human hippocampus and cerebellum”. Brain Res. Mol. Brain Res. 109 (1–2): 168—78. PMID 12531526. doi:10.1016/S0169-328X(02)00557-0.
- O'Malley, K. L.; Jong, YJ; Gonchar, Y.; et al. (2003). „Activation of metabotropic glutamate receptor mGlu5 on nuclear membranes mediates intranuclear Ca2+ changes in heterologous cell types and neurons”. J. Biol. Chem. 278 (30): 28210—9. PMID 12736269. doi:10.1074/jbc.M300792200.
- Corti, C.; Clarkson, RW; Crepaldi, L.; et al. (2003). „Gene structure of the human metabotropic glutamate receptor 5 and functional analysis of its multiple promoters in neuroblastoma and astroglioma cells”. J. Biol. Chem. 278 (35): 33105—19. PMID 12783878. doi:10.1074/jbc.M212380200.
- 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. PMID 12786977. doi:10.1046/j.1460-9568.2003.02657.x.
- Uchino, M.; Sakai, N.; Kashiwagi, K.; et al. (2004). „Isoform-specific phosphorylation of metabotropic glutamate receptor 5 by protein kinase C (PKC) blocks Ca2+ oscillation and oscillatory translocation of Ca2+-dependent PKC”. J. Biol. Chem. 279 (3): 2254—61. PMID 14561742. doi:10.1074/jbc.M309894200.
- Anneser JM, Ince PG, Shaw PJ, Borasio GD (2004). „Differential expression of mGluR5 in human lumbosacral motoneurons”. Neuroreport. 15 (2): 271—3. PMID 15076751. doi:10.1097/00001756-200402090-00012.
- Pacheco, R.; Ciruela, F.; Casadó, V.; et al. (2004). „Group I metabotropic glutamate receptors mediate a dual role of glutamate in T cell activation”. J. Biol. Chem. 279 (32): 33352—8. PMID 15184389. doi:10.1074/jbc.M401761200.
- Kim CH, Braud S, Isaac JT, Roche KW (2005). „Protein kinase C phosphorylation of the metabotropic glutamate receptor mGluR5 on Serine 839 regulates Ca2+ oscillations”. J. Biol. Chem. 280 (27): 25409—15. PMID 15894802. doi:10.1074/jbc.M502644200.
- Cabello, N.; Remelli, R.; Canela, L.; et al. (2007). „Actin-binding protein alpha-actinin-1 interacts with the metabotropic glutamate receptor type 5b and modulates the cell surface expression and function of the receptor”. J. Biol. Chem. 282 (16): 12143—53. PMID 17311919. doi:10.1074/jbc.M608880200.
Spoljašnje veze
- „Metabotropic Glutamate Receptors: mGlu5”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
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Orfan | |
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Drugi | Moždano specifični angiogenezni inhibitor (1, 2, 3) • Kadherin (1, 2, 3) • Kalcitonin • CALCRL • CD97 • Kortikotropin-oslobađajući hormon (1, 2) • EMR (1, 2, 3) • Glukagon (GR, GIPR, GLP1R, GLP2R) • Hormon rasta • PACAPR1 • GPR • Latrofilin (1, 2, 3, ELTD1) • Metuzalemski protein • Paratiroidni hormon (1, 2) • Sekretin • Vazoaktivni intestinalni peptid (1, 2) |
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