Metabotropic glutamate receptor 5

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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 (March 1994). "Molecular cloning and the functional expression of two isoforms of human metabotropic glutamate receptor subtype 5". Biochemical and Biophysical Research Communications. 199 (3): 1136–43. doi:10.1006/bbrc.1994.1349. PMID 7908515.
  2. ↑ 2.0 2.1 "Entrez Gene: GRM5 glutamate receptor, metabotropic 5".
  3. ↑ Chen Y, Goudet C, Pin JP, Conn PJ (March 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". Molecular Pharmacology. 73 (3): 909–18. doi:10.1124/mol.107.040097. PMID 18056795.
  4. ↑ Watkins JC, Jane DE (January 2006). "The glutamate story". British Journal of Pharmacology. 147 Suppl 1 (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 (March 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.
  6. ↑ Bäckström P, Hyytiä P (April 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, Zakharova E, Blokhina E, Zvartau E, Danysz W, van Heeke G, Markou A (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 (September 2008). "mGluR5 antagonists: discovery, characterization and drug development". Current Opinion in Drug Discovery & 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 (January 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 (May 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 (4): 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 & Perspectives. 18 (6): 353–61. doi:10.1358/dnp.2005.18.6.927927. PMID 16247513.
  13. ↑ 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. PMID 15703249.
  14. ↑ Palucha A, Pilc A (July 2007). "Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs". Pharmacology & 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 (August 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 (March 2009). "mGluR5 has a critical role in inhibitory learning". The 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 (August 2009). "mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning". Neuropsychopharmacology. 34 (9): 2057–71. doi:10.1038/npp.2009.30. PMC 2884290. PMID 19295507.
  18. ↑ 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. Autism Spectrum Disorders. New York: Oxford University Press. p. 806. ISBN 978-0-19-5371826.
  19. ↑ 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. PMID 18753411.
  20. ↑ Zhao Z, Wisnoski DD, O'Brien JA, Lemaire W, Williams DL, Jacobson MA, Wittman M, Ha SN, Schaffhauser H, Sur C, Pettibone DJ, Duggan ME, Conn PJ, Hartman GD, Lindsley CW (March 2007). "Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA". Bioorganic & Medicinal Chemistry Letters. 17 (5): 1386–91. doi:10.1016/j.bmcl.2006.11.081. PMID 17210250.
  21. ↑ O'Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD, Lindsley CW, Schaffhauser HJ, Rowe B, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL (May 2004). "A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain". The Journal of Pharmacology and Experimental Therapeutics. 309 (2): 568–77. doi:10.1124/jpet.103.061747. PMID 14747613.
  22. ↑ Chen Y, Nong Y, Goudet C, Hemstapat K, de Paulis T, Pin JP, Conn PJ (May 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". Molecular Pharmacology. 71 (5): 1389–98. doi:10.1124/mol.106.032425. PMID 17303702.
  23. ↑ de Paulis T, Hemstapat K, Chen Y, Zhang Y, Saleh S, Alagille D, Baldwin RM, Tamagnan GD, Conn PJ (June 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". Journal of Medicinal Chemistry. 49 (11): 3332–44. doi:10.1021/jm051252j. PMID 16722652.
  24. ↑ Kinney GG, O'Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK, Chen TB, Wisnoski DD, Lindsley CW, Tiller PR, Smith S, Jacobson MA, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL (April 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". The Journal of Pharmacology and Experimental Therapeutics. 313 (1): 199–206. doi:10.1124/jpet.104.079244. PMID 15608073.
  25. ↑ 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. PMC 4904784. 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". Nature Neuroscience. 4 (9): 873–4. doi:10.1038/nn0901-873. PMID 11528416.
  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.

Further reading

  • 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. PMID 7688218.
  • 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. PMID 8532169.
  • 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. doi:10.1038/386284a0. PMID 9069287.
  • 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. PMID 9242710.
  • 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. PMID 9651375.
  • 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. PMID 9808458.
  • 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. PMID 11943148.
  • 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. PMC 2925652. PMID 11953448.
  • 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. PMID 12119301.
  • 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. PMID 12531512.
  • 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. PMID 12531526.
  • 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. PMID 12736269.
  • 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. PMID 12783878.
  • 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. PMID 12786977.
  • 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. PMID 14561742.
  • 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. PMID 15076751.
  • 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. PMID 15184389.
  • 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. PMID 15894802.
  • 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. PMID 17311919.

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