Metabotropic glutamate receptor 5 explained

Metabotropic glutamate receptor 5 is an excitatory Gq-coupled G protein-coupled receptor[1] predominantly expressed on the postsynaptic sites of neurons.[2] In humans, it is encoded by the GRM5 gene.[3] [4]

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.[4]

There has been extensive research into the role of mGluR5 in psychological disorders, such as addiction[5] and anxiety.[6] 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.[7] A respectable number of potent and selective mGluR5 ligands, which also comprise PET radiotracers, has been developed to date.[8] 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[9] [10] [11] effects in animal studies and their relatively benign safety profile.[12] [13] 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.[14] [15] The clinical use of these drugs may be limited by side effects such as amnesia and psychotomimetic symptoms,[16] [17] [18] [19] but these could be an advantage for some indications,[20] or conversely mGluR5 positive modulators may have nootropic effects.[21]

Agonists

Antagonists

Positive allosteric modulators

Negative allosteric modulators

mGluR5 and addiction

Mice with a knocked out mGluR5 show a lack of cocaine self-administration regardless of dose.[33] 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.[34] This evidence taken together shows that mGluR5 may be crucial for drug-related instrumental self-administration learning, but not conditioned associations.

See also

Further reading

External links

Notes and References

  1. Chu Z, Hablitz JJ . Quisqualate induces an inward current via mGluR activation in neocortical pyramidal neurons . Brain Research . 879 . 1–2 . 88–92 . October 2000 . 11011009 . 10.1016/S0006-8993(00)02752-9 . 16433806 .
  2. Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, Flor PJ, Neki A, Abe T, Nakanishi S, Mizuno N . Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus . The Journal of Neuroscience . 17 . 19 . 7503–22 . October 1997 . 9295396 . 6573434 . 10.1523/JNEUROSCI.17-19-07503.1997.
  3. Minakami R, Katsuki F, Yamamoto T, Nakamura K, Sugiyama H . 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 . March 1994 . 7908515 . 10.1006/bbrc.1994.1349 .
  4. Web site: Entrez Gene: GRM5 glutamate receptor, metabotropic 5.
  5. Brown RM, Mustafa S, Ayoub MA, Dodd PR, Pfleger KD, Lawrence AJ . mGlu5 Receptor Functional Interactions and Addiction . Frontiers in Pharmacology . 3 . 84 . 2012 . 22586398 . 3345582 . 10.3389/fphar.2012.00084 . free .
  6. Tan SZ, Kim JH . mGlu5: A double-edged sword for aversive learning related therapeutics . Neuroanatomy and Behaviour . 2021 . 3 . e16 . 10.35430/nab.2021.e16. free . 11343/281346 . free .
  7. Chen Y, Goudet C, Pin JP, Conn PJ . N--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 . March 2008 . 18056795 . 10.1124/mol.107.040097 . 82273 .
  8. Watkins JC, Jane DE . The glutamate story . British Journal of Pharmacology . 147 . Suppl 1 . S100–8 . January 2006 . 16402093 . 1760733 . 10.1038/sj.bjp.0706444 .
  9. Gass JT, Osborne MP, Watson NL, Brown JL, Olive MF . mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats . Neuropsychopharmacology . 34 . 4 . 820–33 . March 2009 . 18800068 . 2669746 . 10.1038/npp.2008.140 .
  10. Bäckström P, Hyytiä P . Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking . Neuropsychopharmacology . 31 . 4 . 778–86 . April 2006 . 16123768 . 10.1038/sj.npp.1300845 . free .
  11. Bespalov AY, Dravolina OA, Sukhanov I, Zakharova E, Blokhina E, Zvartau E, Danysz W, van Heeke G, Markou A . Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats . Neuropharmacology . 49 . 167–78 . 2005 . Suppl 1 . 16023685 . 10.1016/j.neuropharm.2005.06.007 . 37283433 .
  12. 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 . 5 . 9 . 897–911 . 2005 . 16178734 . 10.2174/1568026054750236 .
  13. Gasparini F, Bilbe G, Gomez-Mancilla B, Spooren W . mGluR5 antagonists: discovery, characterization and drug development . Current Opinion in Drug Discovery & Development . 11 . 5 . 655–65 . September 2008 . 18729017 .
  14. 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 . 450 . 1 . 12–7 . January 2009 . 19027050 . 10.1016/j.neulet.2008.11.026 . 26773751 .
  15. 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 . 29 . 4 . 323–9 . May 2009 . 19153979 . 10.1002/jat.1413 . 22498124 .
  16. Simonyi A, Schachtman TR, Christoffersen GR . The role of metabotropic glutamate receptor 5 in learning and memory processes . Drug News & Perspectives . 18 . 6 . 353–61 . Jul 2005 . 16247513 . 10.1358/dnp.2005.18.6.927927 .
  17. 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 . 15 . 11 . 1703–13 . November 2005 . 15703249 . 10.1093/cercor/bhi047 . free .
  18. Palucha A, Pilc A . Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs . Pharmacology & Therapeutics . 115 . 1 . 116–47 . July 2007 . 17582504 . 10.1016/j.pharmthera.2007.04.007 .
  19. 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 . 191 . 2 . 235–45 . August 2008 . 18471908 . 10.1016/j.bbr.2008.03.032 . 205877961 .
  20. Xu J, Zhu Y, Contractor A, Heinemann SF . mGluR5 has a critical role in inhibitory learning . The Journal of Neuroscience . 29 . 12 . 3676–84 . March 2009 . 19321764 . 2746052 . 10.1523/JNEUROSCI.5716-08.2009 .
  21. 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 . 34 . 9 . 2057–71 . August 2009 . 19295507 . 2884290 . 10.1038/npp.2009.30 .
  22. 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
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  29. 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 . 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 . April 2005 . 15608073 . 10.1124/jpet.104.079244 . 14946765 .
  30. Raboisson P, Breitholtz-Emanuelsson A, Dahllöf H, Edwards L, Heaton WL, Isaac M, Jarvie K, Kers A, Minidis AB, Nordmark A, Sheehan SM, Slassi A, Ström P, Terelius Y, Wensbo D, Wilson JM, Xin T, McLeod DA . 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 . November 2012 . 23046966 . 10.1016/j.bmcl.2012.08.100 .
  31. Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley JN . 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 . April 2012 . 22539775 . 4904784. 10.1126/scitranslmed.3003501 .
  32. Felts AS, Rodriguez AL, Blobaum AL, Morrison RD, Bates BS, Thompson Gray A, Rook JM, Tantawy MN, Byers FW, Chang S, Venable DF, Luscombe VB, Tamagnan GD, Niswender CM, Daniels JS, Jones CK, Conn PJ, Lindsley CW, Emmitte KA . 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 . June 2017 . 28530802 . 10.1021/acs.jmedchem.7b00410 . 5484149 . free .
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  34. Fowler MA, Varnell AL, Cooper DC . mGluR5 knockout mice exhibit normal conditioned place-preference to cocaine . Nature Precedings . August 2011 . 1 . 10101/npre.2011.6180.1 . 10.1038/npre.2011.6180 . 1204.1395 .

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