Metabotropic glutamate receptor 5

Glutamate receptor, metabotropic 5
Identifiers
Symbols	GRM5; GPRC1E; MGLUR5; mGlu5
External IDs	OMIM: 604102 MGI: 1351342 HomoloGene: 37354 IUPHAR: mGlu5 GeneCards: GRM5 Gene
Gene Ontology Molecular function • receptor activity • G-protein coupled receptor activity • glutamate receptor activity • A2A adenosine receptor binding Cellular component • membrane fraction • cytoplasm • plasma membrane • integral to plasma membrane • postsynaptic density • dendritic spine • dendritic shaft Biological process • activation of MAPKKK activity • desensitization of G-protein coupled receptor protein signaling pathway • regulation of transcription, DNA-dependent • protein phosphorylation • activation of protein kinase C activity by G-protein coupled receptor protein signaling pathway • activation of phospholipase C activity by metabotropic glutamate receptor signaling pathway • synaptic transmission • learning • locomotory behavior • negative regulation of locomotion • positive regulation of long-term neuronal synaptic plasticity Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2915	108071
Ensembl	ENSG00000168959	ENSMUSG00000049583
UniProt	P41594	Q3UVX5
RefSeq (mRNA)	NM_000842.3	XM_983330
RefSeq (protein)	NP_000833.1	XP_988424
Location (UCSC)	Chr 11: 88.24 – 88.8 Mb	Chr 7: 94.75 – 95.28 Mb
PubMed search	[1]	[2]

Metabotropic glutamate receptor 5 is a protein 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]

Agonist

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

Positive Allosteric Modulators

• ADX-47273 ^[18]
• CPPHA^[19][20]
• VU-29: K_i = 244 nM, EC₅₀ = 9.0 nM; VU-36: K_i = 95 nM, EC₅₀ = 10.6 nM^[21]
• VU-1545: K_i = 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

• LY-344,545

Negative Allosteric Modulators

• Fenobam
• MPEP
• MTEP: more potent than MPEP

mGluR5 and addiction

Mice with a knocked out mGluR5 show a lack of cocaine self-administration regardless of dose.^[24] 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.^[25] This evidence taken together shows that MgluR5 may be crucial for drug-related instrumental self-administration learning, but not conditioned associations.

See also

• Metabotropic glutamate receptor

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. 
2. ^ ^{a b} "Entrez Gene: GRM5 glutamate receptor, metabotropic 5". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2915. 
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. 
4. ^ Watkins JC, Jane DE. The glutamate story. British Journal of Pharmacology. 2006 Jan;147 Suppl 1:S100-8. doi:10.1038/sj.bjp.0706444 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2669746. 
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. Recent advances in non-competitive mGlu5 receptor antagonists and their potential therapeutic applications. Current Topics in Medicinal Chemistry. 2005;5(9):897-911. PMID 16178734
9. ^ Gasparini F, Bilbe G, Gomez-Mancilla B, Spooren W. mGluR5 antagonists: discovery, characterization and drug development. Current Opinion in Drug Discovery and Development. 2008 Sep;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. The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception. Neuroscience Letters. 2009 Jan 23;450(1):12-7. PMID 19027050
11. ^ Jesse CR, Wilhelm EA, Bortolatto CF, Savegnago L, Nogueira CW. 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. 2009 Jan 19. PMID 19153979
12. ^ Simonyi A, Schachtman TR, Christoffersen GR. The role of metabotropic glutamate receptor 5 in learning and memory processes. Drug News and Perspectives. 2005 Jul-Aug;18(6):353-61. PMID 16247513
13. ^ Manahan-Vaughan D, Braunewell KH. The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity. Cerebral Cortex. 2005 Nov;15(11):1703-13. PMID 15703249
14. ^ Palucha A, Pilc A. Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacology and Therapeutics. 2007 Jul;115(1):116-47. PMID 17582504
15. ^ Christoffersen GR, Simonyi A, Schachtman TR, Clausen B, Clement D, Bjerre VK, Mark LT, Reinholdt M, Schmith-Rasmussen K, Zink LV. mGlu5 antagonism impairs exploration and memory of spatial and non-spatial stimuli in rats. Behavioural Brain Research. 2008 Aug 22;191(2):235-45. PMID 18471908
16. ^ Xu J, Zhu Y, Contractor A, Heinemann SF. mGluR5 has a critical role in inhibitory learning. Journal of Neuroscience. 2009 Mar 25;29(12):3676-84. 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. mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning. Neuropsychopharmacology. 2009 Mar 18. PMID 19295507
18. ^ 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. 
19. ^ 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. 
20. ^ 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. 
21. ^ 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. 
22. ^ 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. 
23. ^ 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. 
24. ^ 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. 
25. ^ Fowler MA, Varnell AL, Cooper DC (August 2011). "mGluR5 knockout mice exhibit normal conditioned place-preference to cocaine". Nature Precedings. doi:10101/npre.2011.6180.1. 

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. PMC 2925652. PMID 11953448. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2925652. 
• 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. 

External links

• "Metabotropic Glutamate Receptors: mGlu₅". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2276. 

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