Metabotropic glutamate receptor 5

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Metabotropic glutamate receptor 5
External IDsOMIM604102 MGI1351342 HomoloGene37354 IUPHAR: mGlu5 GeneCards: GRM5 Gene
RNA expression pattern
More reference expression data
RefSeq (mRNA)NM_000842XM_983330
RefSeq (protein)NP_000833XP_988424
Location (UCSC)Chr 11:
87.88 - 88.42 Mb
Chr 7:
87.48 - 88.01 Mb
PubMed search[1][2]

Metabotropic glutamate receptor 5 is a protein that in humans is encoded by the GRM5 gene.[1][2] 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 pharmacologic 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]


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]


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

Positive Allosteric Modulators

  • 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-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide)[23]
  • DFB (1-(3-fluorophenyl)-N-((3-fluorophenyl)methylideneamino)methanimine)

Orthosteric antagonist

Negative Allosteric Modulators

See also


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External links

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. 
  • 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. 
  • 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. 
  • 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. 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. 
  • 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. 
  • 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. 
  • 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. 
  • 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. 
  • 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. 
  • 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. 
  • 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. 

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

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