Metabotropic glutamate receptor 5

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]

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

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. GRCh38: Ensembl release 89: ENSG00000168959 - Ensembl, May 2017
  2. 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. "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, Shawn Zheng Kai; Kim, Jee Hyun (2021). "mGlu5: A double-edged sword for aversive learning related therapeutics". Neuroanatomy and Behaviour. 3: e16. doi:10.35430/nab.2021.e16.
  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.
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  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.
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  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.
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Further reading

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