Metabotropic glutamate receptor 5
Metabotropic glutamate receptor 5is an excitatoryGq-coupledG protein-coupled receptor[5]predominantly expressed on thepostsynapticsites ofneurons.[6]In humans, it is encoded by theGRM5gene.[7][8]
Function
[edit]The amino acid L-glutamateis the major excitatoryneurotransmitterin the central nervous system and activates bothionotropicandmetabotropicglutamate receptors.Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family ofG protein-coupled receptors,that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacological properties. Group I includesGRM1and GRM5 and these receptors have been shown to activatephospholipase C.Group II includesGRM2andGRM3while Group III includesGRM4,GRM6,GRM7,andGRM8.Group II and III receptors are linked to the inhibition of thecyclic AMP cascadebut differ in their agonist selectivities. Alternative splice variants of GRM8 have been described but their full-length nature has not been determined.[8]
There has been extensive research into the role of mGluR5 in psychological disorders, such as addiction[9]and anxiety.[10]Emerging research strongly points to mGluR5 playing a direct role in the pathogenesis of alcohol use disorder in humans, showing intimate involvement in the development ofbehavioral sensitizationtowards ethanol in animal models.
Ligands
[edit]In addition to the orthosteric site (the site where the endogenous ligand glutamate binds) at least two distinctallostericbinding sitesexist on the mGluR5.[11]A respectable number of potent and selective mGluR5 ligands, which also comprisePETradiotracers,has been developed to date.[12]Selective antagonists and negative allosteric modulators of mGluR5 are a particular area of interest for pharmaceutical research, due to their demonstrated anxiolytic, antidepressant and anti-addictive[13][14][15]effects in animal studies and their relatively benign safety profile.[16][17]mGluR5 receptors are also expressed outside the central nervous system, and mGluR5 antagonists have been shown to be hepatoprotective and may also be useful for the treatment of inflammation and neuropathic pain.[18][19]The clinical use of these drugs may be limited by side effects such as amnesia and psychotomimetic symptoms,[20][21][22][23]but these could be an advantage for some indications,[24]or conversely mGluR5 positive modulators may havenootropiceffects.[25]
Agonists
[edit]Antagonists
[edit]Positive allosteric modulators
[edit]- ADX-47273[28]
- CPPHA[29][30]
- VU-29: Ki= 244 nM, EC50= 9.0 nM; VU-36: Ki= 95 nM, EC50= 10.6 nM[31]
- VU-1545: Ki= 156 nM, EC50= 9.6 nM[32]
- CDPPB(3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide)[33]
- DFB (1-(3-fluorophenyl)-N-((3-fluorophenyl)methylideneamino)methanimine)
Negative allosteric modulators
[edit]- AZD9272[34]
- Basimglurant
- Dipraglurant
- Fenobam
- GRN-529[35]
- MPEP
- MTEP:more potent than MPEP
- Raseglurant
- VU0424238(Tamagnan's name)[36]
- GET73(Fluvoxamine/Zafuleptine) type analog used to treat anxiety and alcoholism.
mGluR5 and addiction
[edit]Mice with aknocked outmGluR5 show a lack ofcocaineself-administration regardless of dose.[37]This suggested that the receptor may be intimately involved in integrating the rewarding properties of cocaine. However, a later study showed that mGluR5 knockout mice responded the same to cocaine reward as wild type mice demonstrated by a cocaine place-preference paradigm.[38]This evidence taken together shows that mGluR5 may be crucial for drug-related instrumental self-administration learning, but not conditioned associations.
See also
[edit]References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000168959–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000049583–Ensembl,May 2017
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- ^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.doi:10.2174/1568026054750236.PMID16178734.
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- ^Manahan-Vaughan D, Braunewell KH (November 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.doi:10.1093/cercor/bhi047.PMID15703249.
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- ^Chen ANY, Hellyer SD, Trinh PNH, Leach K, Gregory KJ (2019): Identification of monellin as the first naturally derived proteinaceous allosteric agonist of metabotropic glutamate receptor 5.Basic Clin Pharmacol Toxicol.PMID 30983151
- ^Hagerman RJ, Narcisa V, Hagerman PJ (2011)."Fragile X: A Molecular and Treatment Model for Autism Spectrum Disorders".In Geschwind DH, Dawson G, Amaral DG (eds.).Autism Spectrum Disorders.New York: Oxford University Press. p. 806.ISBN978-0-19-5371826.
- ^Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G, Atkinson PJ, Popiolek M, Wantuch C, Khawaja X, Smith D, Olsen M, Kouranova E, Lai M, Pruthi F, Pulicicchio C, Day M, Gilbert A, Pausch MH, Brandon NJ, Beyer CE, Comery TA, Logue S, Rosenzweig-Lipson S, Marquis KL (December 2008). "ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities".The Journal of Pharmacology and Experimental Therapeutics.327(3): 827–39.doi:10.1124/jpet.108.136580.PMID18753411.S2CID19362501.
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- ^Raboisson P, Breitholtz-Emanuelsson A, Dahllöf H, Edwards L, Heaton WL, Isaac M, et al. (November 2012). "Discovery and characterization of AZD9272 and AZD6538-Two novel mGluR5 negative allosteric modulators selected for clinical development".Bioorganic & Medicinal Chemistry Letters.22(22): 6974–6979.doi:10.1016/j.bmcl.2012.08.100.PMID23046966.
- ^Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley JN (April 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.PMC4904784.PMID22539775.
- ^Felts AS, Rodriguez AL, Blobaum AL, Morrison RD, Bates BS, Thompson Gray A, et al. (June 2017)."Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation".Journal of Medicinal Chemistry.60(12): 5072–5085.doi:10.1021/acs.jmedchem.7b00410.PMC5484149.PMID28530802.
- ^Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F (September 2001). "Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice".Nature Neuroscience.4(9): 873–4.doi:10.1038/nn0901-873.PMID11528416.S2CID1314227.
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Further reading
[edit]- Minakami R, Katsuki F, Sugiyama H (July 1993). "A variant of metabotropic glutamate receptor subtype 5: an evolutionally conserved insertion with no termination codon".Biochemical and Biophysical Research Communications.194(2): 622–7.doi:10.1006/bbrc.1993.1866.PMID7688218.
- Daggett LP, Sacaan AI, Akong M, Rao SP, Hess SD, Liaw C, Urrutia A, Jachec C, Ellis SB, Dreessen J (August 1995). "Molecular and functional characterization of recombinant human metabotropic glutamate receptor subtype 5".Neuropharmacology.34(8): 871–86.doi:10.1016/0028-3908(95)00085-K.PMID8532169.S2CID12710570.
- Brakeman PR, Lanahan AA, O'Brien R, Roche K, Barnes CA, Huganir RL, Worley PF (March 1997). "Homer: a protein that selectively binds metabotropic glutamate receptors".Nature.386(6622): 284–8.Bibcode:1997Natur.386..284B.doi:10.1038/386284a0.PMID9069287.S2CID4346579.
- Minakami R, Jinnai N, Sugiyama H (August 1997)."Phosphorylation and calmodulin binding of the metabotropic glutamate receptor subtype 5 (mGluR5) are antagonistic in vitro".The Journal of Biological Chemistry.272(32): 20291–8.doi:10.1074/jbc.272.32.20291.PMID9242710.
- Snow BE, Hall RA, Krumins AM, Brothers GM, Bouchard D, Brothers CA, Chung S, Mangion J, Gilman AG, Lefkowitz RJ, Siderovski DP (July 1998)."GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain".The Journal of Biological Chemistry.273(28): 17749–55.doi:10.1074/jbc.273.28.17749.PMID9651375.
- Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder CD, Ruggiero A, Lanahan AA, Wenthold RJ, Worley PF (October 1998)."Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins".Neuron.21(4): 707–16.doi:10.1016/S0896-6273(00)80588-7.PMID9808458.S2CID16431031.
- Enz R (March 2002)."The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7".FEBS Letters.514(2–3): 184–8.doi:10.1016/S0014-5793(02)02361-X.PMID11943148.S2CID44474808.
- Saugstad JA, Yang S, Pohl J, Hall RA, Conn PJ (March 2002)."Interaction between metabotropic glutamate receptor 7 and alpha tubulin".Journal of Neurochemistry.80(6): 980–8.doi:10.1046/j.0022-3042.2002.00778.x.PMC2925652.PMID11953448.
- Nash MS, Schell MJ, Atkinson PJ, Johnston NR, Nahorski SR, Challiss RA (September 2002)."Determinants of metabotropic glutamate receptor-5-mediated Ca2+ and inositol 1,4,5-trisphosphate oscillation frequency. Receptor density versus agonist concentration".The Journal of Biological Chemistry.277(39): 35947–60.doi:10.1074/jbc.M205622200.PMID12119301.
- Bates B, Xie Y, Taylor N, Johnson J, Wu L, Kwak S, Blatcher M, Gulukota K, Paulsen JE (December 2002). "Characterization of mGluR5R, a novel, metabotropic glutamate receptor 5-related gene".Brain Research. Molecular Brain Research.109(1–2): 18–33.doi:10.1016/S0169-328X(02)00458-8.PMID12531512.
- Malherbe P, Kew JN, Richards JG, Knoflach F, Kratzeisen C, Zenner MT, Faull RL, Kemp JA, Mutel V (December 2002). "Identification and characterization of a novel splice variant of the metabotropic glutamate receptor 5 gene in human hippocampus and cerebellum".Brain Research. Molecular Brain Research.109(1–2): 168–78.doi:10.1016/S0169-328X(02)00557-0.PMID12531526.
- O'Malley KL, Jong YJ, Gonchar Y, Burkhalter A, Romano C (July 2003)."Activation of metabotropic glutamate receptor mGlu5 on nuclear membranes mediates intranuclear Ca2+ changes in heterologous cell types and neurons".The Journal of Biological Chemistry.278(30): 28210–9.doi:10.1074/jbc.M300792200.PMID12736269.
- Corti C, Clarkson RW, Crepaldi L, Sala CF, Xuereb JH, Ferraguti F (August 2003)."Gene structure of the human metabotropic glutamate receptor 5 and functional analysis of its multiple promoters in neuroblastoma and astroglioma cells".The Journal of Biological Chemistry.278(35): 33105–19.doi:10.1074/jbc.M212380200.PMID12783878.
- Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, Troost D (May 2003). "Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins".The European Journal of Neuroscience.17(10): 2106–18.doi:10.1046/j.1460-9568.2003.02657.x.PMID12786977.S2CID23408003.
- Uchino M, Sakai N, Kashiwagi K, Shirai Y, Shinohara Y, Hirose K, Iino M, Yamamura T, Saito N (January 2004)."Isoform-specific phosphorylation of metabotropic glutamate receptor 5 by protein kinase C (PKC) blocks Ca2+ oscillation and oscillatory translocation of Ca2+-dependent PKC".The Journal of Biological Chemistry.279(3): 2254–61.doi:10.1074/jbc.M309894200.PMID14561742.
- Anneser JM, Ince PG, Shaw PJ, Borasio GD (February 2004). "Differential expression of mGluR5 in human lumbosacral motoneurons".NeuroReport.15(2): 271–3.doi:10.1097/00001756-200402090-00012.PMID15076751.S2CID31001609.
- Pacheco R, Ciruela F, Casadó V, Mallol J, Gallart T, Lluis C, Franco R (August 2004)."Group I metabotropic glutamate receptors mediate a dual role of glutamate in T cell activation".The Journal of Biological Chemistry.279(32): 33352–8.doi:10.1074/jbc.M401761200.hdl:2445/176929.PMID15184389.
- Kim CH, Braud S, Isaac JT, Roche KW (July 2005)."Protein kinase C phosphorylation of the metabotropic glutamate receptor mGluR5 on Serine 839 regulates Ca2+ oscillations".The Journal of Biological Chemistry.280(27): 25409–15.doi:10.1074/jbc.M502644200.PMID15894802.
- Cabello N, Remelli R, Canela L, Soriguera A, Mallol J, Canela EI, Robbins MJ, Lluis C, Franco R, McIlhinney RA, Ciruela F (April 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".The Journal of Biological Chemistry.282(16): 12143–53.doi:10.1074/jbc.M608880200.hdl:2445/122383.PMID17311919.
External links
[edit]- "Metabotropic Glutamate Receptors: mGlu5".IUPHAR Database of Receptors and Ion Channels.International Union of Basic and Clinical Pharmacology.
This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.