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Metabotropic glutamate receptor 5

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Template:PBB Metabotropic glutamate receptor 5 is a G protein-coupled receptor that in humans is encoded by the GRM5 gene.[1][2]

Function

The amino acid L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate 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 of G 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 includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7, and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Alternative splice variants of GRM8 have been described but their full-length nature has not been determined.[2]

Ligands

In addition to the orthosteric site (the site where the endogenous ligand glutamate binds) at least two distinct allosteric binding sites exist on the mGluR5.[3] A respectable number of potent and selective mGluR5 ligands, which also comprise PET radiotracers, has been developed to date.[4] 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[5][6][7] effects in animal studies and their relatively benign safety profile.[8][9] 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.[10][11] The clinical use of these drugs may be limited by side effects such as amnesia and psychotomimetic symptoms,[12][13][14][15] but these could be an advantage for some indications,[16] or conversely mGluR5 positive modulators may have nootropic effects.[17]

Agonists

  • CHPG (2-amino-2-(2-chloro-5-hydroxyphenyl)acetic acid)

Antagonists

Positive allosteric modulators

  • ADX-47273 [19]
  • CPPHA[20][21]
  • VU-29: Ki = 244 nM, EC50 = 9.0 nM; VU-36: Ki = 95 nM, EC50 = 10.6 nM[22]
  • VU-1545: Ki = 156 nM, EC50 = 9.6 nM[23]
  • CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide)[24]
  • DFB (1-(3-fluorophenyl)-N-((3-fluorophenyl)methylideneamino)methanimine)

Orthosteric antagonists

Negative allosteric modulators

mGluR5 and addiction

Mice with a knocked out mGluR5 show a lack of cocaine self-administration regardless of dose.[26] This suggested that the receptor may be intimately involved in 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.[27] This evidence taken together shows that mGluR5 may be crucial for drug-related instrumental self-administration learning, but not conditioned associations.

See also

References

  1. ^ Minakami R, Katsuki F, Yamamoto T, Nakamura K, Sugiyama H (May 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. doi:10.1006/bbrc.1994.1349. PMID 7908515.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ a b "Entrez Gene: GRM5 glutamate receptor, metabotropic 5".
  3. ^ Chen Y, Goudet C, Pin JP, Conn PJ (2008). "N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors". Mol. Pharmacol. 73 (3): 909–18. doi:10.1124/mol.107.040097. PMID 18056795.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Watkins JC, Jane DE (Jan 2006). "The glutamate story". British Journal of Pharmacology. 147 (Suppl 1): S100–8. doi:10.1038/sj.bjp.0706444. PMC 1760733. PMID 16402093.
  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. doi:10.1038/npp.2008.140. PMC 2669746. PMID 18800068.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Bäckström P, Hyytiä P (2006). "Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking". Neuropsychopharmacology. 31 (4): 778–86. doi:10.1038/sj.npp.1300845. PMID 16123768.
  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. doi:10.1016/j.neuropharm.2005.06.007. PMID 16023685.
  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. doi:10.2174/1568026054750236. PMID 16178734.
  9. ^ Gasparini F, Bilbe G, Gomez-Mancilla B, Spooren W (Sep 2008). "mGluR5 antagonists: discovery, characterization and drug development". Current Opinion in Drug Discovery and Development. 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 (Jan 2009). "The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception". Neuroscience Letters. 450 (1): 12–7. doi:10.1016/j.neulet.2008.11.026. PMID 19027050.
  11. ^ Jesse CR, Wilhelm EA, Bortolatto CF, Savegnago L, Nogueira CW (Jan 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. 29: 323–9. doi:10.1002/jat.1413. PMID 19153979.
  12. ^ Simonyi A, Schachtman TR, Christoffersen GR (Jul 2005). "The role of metabotropic glutamate receptor 5 in learning and memory processes". Drug News and Perspectives. 18 (6): 353–61. doi:10.1358/dnp.2005.18.6.927927. PMID 16247513.
  13. ^ Manahan-Vaughan D, Braunewell KH (Nov 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. PMID 15703249.
  14. ^ Palucha A, Pilc A (Jul 2007). "Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs". Pharmacology and Therapeutics. 115 (1): 116–47. doi:10.1016/j.pharmthera.2007.04.007. PMID 17582504.
  15. ^ Christoffersen GR, Simonyi A, Schachtman TR, Clausen B, Clement D, Bjerre VK, Mark LT, Reinholdt M, Schmith-Rasmussen K, Zink LV (Aug 2008). "mGlu5 antagonism impairs exploration and memory of spatial and non-spatial stimuli in rats". Behavioural Brain Research. 191 (2): 235–45. doi:10.1016/j.bbr.2008.03.032. PMID 18471908.
  16. ^ Xu J, Zhu Y, Contractor A, Heinemann SF (Mar 2009). "mGluR5 has a critical role in inhibitory learning". Journal of Neuroscience. 29 (12): 3676–84. doi:10.1523/JNEUROSCI.5716-08.2009. PMC 2746052. 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 (2009). "mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning". Neuropsychopharmacology. 34: 2057–71. doi:10.1038/npp.2009.30. PMC 2884290. PMID 19295507.
  18. ^ [1]
  19. ^ 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-yl}-methanone]: 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. doi:10.1124/jpet.108.136580. PMID 18753411.
  20. ^ 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. doi:10.1016/j.bmcl.2006.11.081. PMID 17210250.
  21. ^ 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. doi:10.1124/jpet.103.061747. PMID 14747613.
  22. ^ 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. doi:10.1124/mol.106.032425. PMID 17303702.
  23. ^ 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. doi:10.1021/jm051252j. PMID 16722652.
  24. ^ 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. doi:10.1124/jpet.104.079244. PMID 15608073.
  25. ^ Silverman, J. L.; Smith, D. G.; Rizzo, S. J. S.; Karras, M. N.; Turner, S. M.; Tolu, S. S.; Bryce, D. K.; Smith, D. L.; Fonseca, K.; Ring, R. H.; Crawley, J. N. (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. PMID 22539775.
  26. ^ 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". Nat. Neurosci. 4 (9): 873–4. doi:10.1038/nn0901-873. PMID 11528416.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ^ Fowler MA, Varnell AL, Cooper DC (August 2011). "mGluR5 knockout mice exhibit normal conditioned place-preference to cocaine". Nature Precedings. hdl:10101/npre.2011.6180.1.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

  • 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. doi:10.1006/bbrc.1993.1866. PMID 7688218.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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. doi:10.1016/0028-3908(95)00085-K. PMID 8532169.
  • Brakeman PR, Lanahan AA, O'Brien R, et al. (1997). "Homer: a protein that selectively binds metabotropic glutamate receptors". Nature. 386 (6622): 284–8. doi:10.1038/386284a0. PMID 9069287.
  • 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. doi:10.1074/jbc.272.32.20291. PMID 9242710.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  • 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. doi:10.1074/jbc.273.28.17749. PMID 9651375.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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. doi:10.1016/S0896-6273(00)80588-7. PMID 9808458.
  • Enz R (2002). "The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7". FEBS Lett. 514 (2–3): 184–8. doi:10.1016/S0014-5793(02)02361-X. PMID 11943148.
  • Saugstad JA, Yang S, Pohl J, et al. (2002). "Interaction between metabotropic glutamate receptor 7 and alpha tubulin". J. Neurochem. 80 (6): 980–8. doi:10.1046/j.0022-3042.2002.00778.x. PMC 2925652. PMID 11953448.
  • 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. doi:10.1074/jbc.M205622200. PMID 12119301.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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. doi:10.1016/S0169-328X(02)00458-8. PMID 12531512.
  • 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. doi:10.1016/S0169-328X(02)00557-0. PMID 12531526.
  • 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. doi:10.1074/jbc.M300792200. PMID 12736269.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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. doi:10.1074/jbc.M212380200. PMID 12783878.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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.
  • 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. doi:10.1074/jbc.M309894200. PMID 14561742.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Anneser JM, Ince PG, Shaw PJ, Borasio GD (2004). "Differential expression of mGluR5 in human lumbosacral motoneurons". NeuroReport. 15 (2): 271–3. doi:10.1097/00001756-200402090-00012. PMID 15076751.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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. doi:10.1074/jbc.M401761200. PMID 15184389.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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. doi:10.1074/jbc.M502644200. PMID 15894802.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  • 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. doi:10.1074/jbc.M608880200. PMID 17311919.{{cite journal}}: CS1 maint: unflagged free DOI (link)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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