GRM5
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGRM5, GPRC1E, MGLUR5, PPP1R86, mGlu5, glutamate metabotropic receptor 5
External IDsOMIM: 604102 MGI: 1351342 HomoloGene: 37354 GeneCards: GRM5
Orthologs
SpeciesHumanMouse
Entrez

2915

108071

Ensembl

ENSG00000168959

ENSMUSG00000049583

UniProt

P41594

Q3UVX5

RefSeq (mRNA)

NM_000842
NM_001143831
NM_001384268

NM_001033224
NM_001081414
NM_001143834

RefSeq (protein)

NP_000833
NP_001137303

NP_001074883
NP_001137306

Location (UCSC)Chr 11: 88.5 – 89.07 MbChr 7: 87.23 – 87.78 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Metabotropic glutamate receptor 5 is an excitatory Gq-coupled G protein-coupled receptor[5] predominantly expressed on the postsynaptic sites of neurons.[6] In humans, it is encoded by the GRM5 gene.[7][8]

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.[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 of behavioral sensitization towards ethanol in animal models.

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.[11] A respectable number of potent and selective mGluR5 ligands, which also comprise PET radiotracers, 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 have nootropic effects.[25]

Agonists

Antagonists

Positive allosteric modulators

  • 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

mGluR5 and addiction

Mice with a knocked out mGluR5 show a lack of cocaine self-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

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000168959 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000049583 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Chu Z, Hablitz JJ (October 2000). "Quisqualate induces an inward current via mGluR activation in neocortical pyramidal neurons". Brain Research. 879 (1–2): 88–92. doi:10.1016/S0006-8993(00)02752-9. PMID 11011009. S2CID 16433806.
  6. ↑ Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, Flor PJ, Neki A, Abe T, Nakanishi S, Mizuno N (October 1997). "Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus". The Journal of Neuroscience. 17 (19): 7503–22. doi:10.1523/JNEUROSCI.17-19-07503.1997. PMC 6573434. PMID 9295396.
  7. ↑ 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.
  8. 1 2 "Entrez Gene: GRM5 glutamate receptor, metabotropic 5".
  9. ↑ Brown RM, Mustafa S, Ayoub MA, Dodd PR, Pfleger KD, Lawrence AJ (2012). "mGlu5 Receptor Functional Interactions and Addiction". Frontiers in Pharmacology. 3: 84. doi:10.3389/fphar.2012.00084. PMC 3345582. PMID 22586398.
  10. ↑ Tan SZ, Kim JH (2021). "mGlu5: A double-edged sword for aversive learning related therapeutics". Neuroanatomy and Behaviour. 3: e16. doi:10.35430/nab.2021.e16. hdl:11343/281346.
  11. ↑ 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. S2CID 82273.
  12. ↑ Watkins JC, Jane DE (January 2006). "The glutamate story". British Journal of Pharmacology. 147 (Suppl 1): S100–8. doi:10.1038/sj.bjp.0706444. PMC 1760733. PMID 16402093.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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. S2CID 37283433.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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. S2CID 26773751.
  19. ↑ 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. S2CID 22498124.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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. S2CID 205877961.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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
  27. ↑ 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. ISBN 978-0-19-5371826.
  28. ↑ 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. S2CID 19362501.
  29. ↑ 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.
  30. ↑ 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. S2CID 10103555.
  31. ↑ 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. S2CID 7004830.
  32. ↑ 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.
  33. ↑ 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. S2CID 14946765.
  34. ↑ 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. PMID 23046966.
  35. ↑ 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.
  36. ↑ 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. PMC 5484149. PMID 28530802.
  37. ↑ 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. S2CID 1314227.
  38. ↑ Fowler MA, Varnell AL, Cooper DC (August 2011). "mGluR5 knockout mice exhibit normal conditioned place-preference to cocaine". Nature Precedings: 1. arXiv:1204.1395. doi:10.1038/npre.2011.6180. hdl:10101/npre.2011.6180.1.

Further reading

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