Metabotropni glutamatni receptor 5

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

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

  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 (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. 
  9. ^ 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 |title= (помоћ)
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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: |date= (помоћ)
  13. ^ 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. 
  14. ^ 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. 
  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. 191 (2): 235—45. август 2008. PMID 18471908.  Недостаје или је празан параметар |title= (помоћ)
  16. ^ 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 |title= (помоћ)
  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, 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. 
  20. ^ 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. 
  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, 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. 
  24. ^ 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. 
  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

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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. 
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German footballer Jan Hochscheidt Hochscheidt in 2016Personal informationDate of birth (1987-10-04) 4 October 1987 (age 36)Place of birth Trier, West GermanyHeight 1.79 m (5 ft 10 in)Position(s) MidfielderYouth career1994–2000 Hertha Zehlendorf2000–2004 Union Berlin2004–2006 Energie CottbusSenior career*Years Team Apps (Gls)2006–2008 Energie Cottbus II 42 (5)2008–2013 Erzgebirge Aue 164 (26)2013–2018 Eintracht Braunschweig 109 (12)2014 → Eintracht Braunschwei...

 

Washington State Route 528

State highway in Marysville, Washington, U.S. State Route 5284th Street64th StreetSR 528 highlighted in red.Route informationAuxiliary route of I-5Maintained by WSDOTLength3.46 mi[1] (5.57 km)Existed1964[2]–presentMajor junctionsWest end I-5 in MarysvilleMajor intersections SR 529 in MarysvilleEast end SR 9 in Marysville LocationCountryUnited StatesStateWashingtonCountySnohomish Highway system State highways in Washington Interstate US...

 

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Culinary traditions of Apulia, Italy Italian cuisine History Ancient Roman cuisine Medieval cuisine Early modern cuisine Contemporary cuisine Regional cuisines Abruzzese cuisine Apulian cuisine Arbëreshë cuisine Corsican cuisine Ligurian cuisine Lombard cuisine Mantuan cuisine Lucanian cuisine Neapolitan cuisine Piedmontese cuisine Roman cuisine Sardinian cuisine Sicilian cuisine Venetian cuisine Lists Chefs Dishes Pasta Cheeses PDO Desserts and pastries Restaurants Wine IGT DOCG DOC Beer S...

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President of the United States from 1881 to 1885 Chester Alan Arthur and Chester Arthur redirect here. For his son, see Chester Alan Arthur II. For his grandson, see Gavin Arthur. Chester A. Arthur21st President of the United StatesIn officeSeptember 19, 1881 – March 4, 1885Vice PresidentNone[a]Preceded byJames A. GarfieldSucceeded byGrover Cleveland20th Vice President of the United StatesIn officeMarch 4, 1881 – September 19, 1881PresidentJames A. Garfie...

 

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