Metabotropni glutamatni receptor 5

С Википедије, слободне енциклопедије
Glutamatni receptor, metabotropni 5
Dostupne strukture
3LMK​
Identifikatori
Simboli GRM5; GPRC1E; MGLUR5; mGlu5
Vanjski ID OMIM: 604102 MGI: 1351342 HomoloGene: 37354 IUPHAR: mGlu5 GeneCards: GRM5 Gene
Pregled RNK izražavanja
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[уреди | уреди извор]

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[уреди | уреди извор]

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[уреди | уреди извор]

  • CHPG (2-amino-2-(2-hloro-5-hidroksifenil)sirćetna kiselina)

Antagonist[уреди | уреди извор]

Pozitivni alosterni modulatori[уреди | уреди извор]

  • 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[уреди | уреди извор]

Negativni alosterni modulatori[уреди | уреди извор]

mGluR5 i adikcija[уреди | уреди извор]

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[уреди | уреди извор]

Reference[уреди | уреди извор]

  1. ^ 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. 
  2. ^ а б „Entrez Gene: GRM5 glutamate receptor, metabotropic 5”. 
  3. ^ 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. 
  4. ^ 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 |title= (помоћ)
  5. ^ 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 Слободан приступ. PMID 18800068. doi:10.1038/npp.2008.140. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ Slassi A, Isaac M, Edwards L, Minidis A, Wensbo D, Mattsson J, Nilsson K, Raboisson P, McLeod D, Stormann TM, Hammerland LG, Johnson E. Recent advances in non-competitive mGlu5 receptor antagonists and their potential therapeutic applications. Current Topics in Medicinal Chemistry. 2005;5(9):897-911. PMID 16178734
  9. ^ Gasparini F, Bilbe G, Gomez-Mancilla B, Spooren W. mGluR5 antagonists: discovery, characterization and drug development. Current Opinion in Drug Discovery and Development. 2008 Sep;11(5):655-65. PMID 18729017
  10. ^ Hu Y, Dong L, Sun B, Guillon MA, Burbach LR, Nunn PA, Liu X, Vilenski O, Ford AP, Zhong Y, Rong W. The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception. Neuroscience Letters. 2009 Jan 23;450(1):12-7. PMID 19027050
  11. ^ Jesse CR, Wilhelm EA, Bortolatto CF, Savegnago L, Nogueira CW. 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. 2009 Jan 19. PMID 19153979
  12. ^ Simonyi A, Schachtman TR, Christoffersen GR. The role of metabotropic glutamate receptor 5 in learning and memory processes. Drug News and Perspectives. 2005 Jul-Aug;18(6):353-61. PMID 16247513
  13. ^ Manahan-Vaughan D, Braunewell KH. The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity. Cerebral Cortex. 2005 Nov;15(11):1703-13. PMID 15703249
  14. ^ Palucha A, Pilc A. Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacology and Therapeutics. 2007 Jul;115(1):116-47. PMID 17582504
  15. ^ 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. 2008 Aug 22;191(2):235-45. PMID 18471908
  16. ^ Xu J, Zhu Y, Contractor A, Heinemann SF. mGluR5 has a critical role in inhibitory learning. Journal of Neuroscience. 2009 Mar 25;29(12):3676-84. PMID 19321764
  17. ^ 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
  18. ^ 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. 
  19. ^ Zhao Z; Wisnoski, DD; O'Brien JA; 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. 
  20. ^ O'Brien JA; 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. 
  21. ^ 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. 
  22. ^ 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. 
  23. ^ Kinney, GG; O'Brien JA; 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. 
  24. ^ Silverman, J. L. (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. 
  25. ^ 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. 
  26. ^ Fowler MA, Varnell AL, Cooper DC (2011). „mGluR5 knockout mice exhibit normal conditioned place-preference to cocaine”. Nature Precedings. 

Literatura[уреди | уреди извор]

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  • 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 Слободан приступ. 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 KL; 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. 
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  • 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[уреди | уреди извор]

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