Biology:Metabotropic glutamate receptor 2

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the GRM2 gene.[1][2] mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit.[3] The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.

Structure

In humans, mGluR2 is encoded by the GRM2 gene on chromosome 3. At least three protein-coding isoforms are predicted based on genomic information, as well as numerous non-coding isoforms. The mGluR2 protein is a seven-pass transmembrane protein.

Function

In humans, mGluR2 is only expressed in the brain, and not in any other tissue.[4] In the brain, mGluR2 is expressed in neurons as well as astrocytes. Subcellularly, mGluR2 is predominantly positioned at the presynaptic terminal, although it is also expressed at the postsynaptic terminal.[5]

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 mGluR2 (this receptor) 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.[2]

Protein–protein interactions

mGluR2 is able to form a heteromeric complex with various other different GPCRs. One example is with isoform mGluR4. The mGluR2-mGluR4 heteromer exhibits a pharmacological profile distinct from the parent receptor monomers.[6] Another example is with serotonin receptor 2A (5HT2A); see below.

Pharmacology

The development of subtype-2-selective positive allosteric modulators (PAMs) experienced steady advance in recent years.[7] mGluR2 potentiation is a new approach for the treatment of schizophrenia.[8][9] On the other hand, antagonists and negative allosteric modulators of mGluR2/3 have potential as antidepressant drugs.[10][11][12][13][14]

Agonists

  • Compound 1d (see reference)[15][16]
  • LY-2812223

PAMs

Highly selective mGluR2 PAM (2010),[17] analog of BINA
  • JNJ-46356479[18]
  • JNJ-40411813[19]
  • GSK-1331258[20]
  • Imidazo[1,2-a]pyridines[21]
  • 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones[22]
  • 3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: potent, orally stable[23]
  • BINA:[24][25] potent; modest ago-allosteric modulator; robust in-vivo activity.
  • LY-487,379:[26][27][28] devoid of orthosteric activity; along with related 3-pyridylmethylsulfonamides[29][30] the first subtype-2-selective potentiator published (2003).

Antagonists

  • LY-341,495
  • MGS-0039
  • EGLU

NAMs

  • 7,8-dichloro-4-[3-(2-methylpyridin-4-yl)phenyl]-1,3-dihydro-1,5-benzodiazepin-2-one and related compounds.[31]
  • MNI-137 - 8-bromo-4-(2-cyanopyridin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one[32]
  • RO4491533 - 4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one[33]

Role in hallucinogenesis

Many psychedelic drugs (e.g. LSD-25) produce their effects by binding to the oligomerized complexes of the 5HT2A and mGlu2 receptors.[34][35] Lisuride acts preferentially or exclusively on the non-heteromerized 5HT2A receptors, which are not capable of inducing psychedelic effects. Due to this, lisuride is capable of reducing the hallucinogenic effects of these drugs through competitive antagonistic activity (producing the effect of a silent antagonist in the presence of these drugs).

Strong agonists for either subunit of the 5HT2A-mGlu2R heterocomplex suppress signaling through the partner subunit and inverse agonists for either subunit potentiate the signaling through the partner subunit.

Role in rabies virus infection

mGluR2 has been found to be a novel receptor for rabies virus.[36] The virus has a glycoprotein on its surface which interacts with the receptor. Rabies virus can bind to mGLuR2 directly and the virus-receptor complex is internalized into the cell together. The complex is then transported into early and late endosomes. Rabies virus enters the cells by clathrin-independent endocytosis which could suggest that mGLuR2 also uses this pathway. It is still to be clarified whether the Rabies virus glycoprotein can act as a PAM or NAM and in such a way affect the function of the receptor.

See also

References

  1. ↑ "Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2". The European Journal of Neuroscience 7 (4): 622–9. April 1995. doi:10.1111/j.1460-9568.1995.tb00666.x. PMID 7620613. 
  2. ↑ 2.0 2.1 "Entrez Gene: GRM2 glutamate receptor, metabotropic 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2912. 
  3. ↑ "Specificity of metabotropic glutamate receptor 2 coupling to G proteins". Molecular Pharmacology 63 (1): 183–91. January 2003. doi:10.1124/mol.63.1.183. PMID 12488551. 
  4. ↑ "Tissue expression of GRM2 - Summary - The Human Protein Atlas". http://www.proteinatlas.org/ENSG00000164082-GRM2/tissue. 
  5. ↑ "mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions". Molecular Psychiatry 22 (11): 1615–1625. November 2017. doi:10.1038/mp.2016.129. PMID 27502475. 
  6. ↑ "Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS". The Journal of Neuroscience 34 (1): 79–94. January 2014. doi:10.1523/JNEUROSCI.1129-13.2014. PMID 24381270. 
  7. ↑ "Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia". Expert Opinion on Therapeutic Patents 19 (9): 1259–75. September 2009. doi:10.1517/13543770903045009. PMID 19552508. 
  8. ↑ "Promise of mGluR2/3 activators in psychiatry". Neuropsychopharmacology 34 (1): 248–9. January 2009. doi:10.1038/npp.2008.156. PMID 19079073. 
  9. ↑ "Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs". Frontiers in Pharmacology 7: 130. 2016. doi:10.3389/fphar.2016.00130. PMID 27242534. 
  10. ↑ "Neuropharmacological profiles of antagonists of group II metabotropic glutamate receptors". Neuroscience Letters 378 (3): 131–4. April 2005. doi:10.1016/j.neulet.2004.12.021. PMID 15781145. 
  11. ↑ "Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression". European Journal of Pharmacology 592 (1–3): 96–102. September 2008. doi:10.1016/j.ejphar.2008.06.089. PMID 18634781. 
  12. ↑ "mTOR activation is required for the antidepressant effects of mGluR₂/₃ blockade". The International Journal of Neuropsychopharmacology 15 (4): 429–34. May 2012. doi:10.1017/S1461145711001702. PMID 22114864. 
  13. ↑ "Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression". Behavioural Brain Research 238: 48–52. February 2013. doi:10.1016/j.bbr.2012.10.023. PMID 23098797. 
  14. ↑ "5-HT1A receptor stimulation in the medial prefrontal cortex mediates the antidepressant effects of mGlu2/3 receptor antagonist in mice". Neuropharmacology 137: 96–103. May 2018. doi:10.1016/j.neuropharm.2018.05.001. PMID 29738849. 
  15. ↑ "New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III". Journal of Medicinal Chemistry 59 (3): 914–24. February 2016. doi:10.1021/acs.jmedchem.5b01333. PMID 26814576. 
  16. ↑ "Synthesis and Pharmacological Characterization of C4β-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1S,2S,4S,5R,6S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu3 Receptor Agonist". Journal of Medicinal Chemistry 61 (6): 2303–2328. 2018. doi:10.1021/acs.jmedchem.7b01481. PMID 29350927. 
  17. ↑ "Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats". Journal of Medicinal Chemistry 54 (1): 342–53. January 2011. doi:10.1021/jm1012165. PMID 21155570. 
  18. ↑ "Discovery of 8-Trifluoromethyl-3-cyclopropylmethyl-7-[(4-(2,4-difluorophenyl)-1-piperazinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine (JNJ-46356479), a Selective and Orally Bioavailable mGlu2 Receptor Positive Allosteric Modulator (PAM)". Journal of Medicinal Chemistry 59 (18): 8495–507. September 2016. doi:10.1021/acs.jmedchem.6b00913. PMID 27579727. 
  19. ↑ "addextherapeutics – ADX71149 for schizophrenia". http://www.addextherapeutics.com/rd/pipeline/adx71149-for-schizophrenia/. 
  20. ↑ "The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2". Bioorganic & Medicinal Chemistry Letters 20 (2): 759–62. January 2010. doi:10.1016/j.bmcl.2009.11.032. PMID 20005096. 
  21. ↑ "Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor". Bioorganic & Medicinal Chemistry Letters 20 (1): 175–9. January 2010. doi:10.1016/j.bmcl.2009.11.008. PMID 19932615. 
  22. ↑ "3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts". Bioorganic & Medicinal Chemistry Letters 20 (10): 3129–33. May 2010. doi:10.1016/j.bmcl.2010.03.089. PMID 20409708. 
  23. ↑ "3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: a novel series of mGluR2 positive allosteric modulators". Bioorganic & Medicinal Chemistry Letters 18 (20): 5493–6. October 2008. doi:10.1016/j.bmcl.2008.09.026. PMID 18812259. 
  24. ↑ "Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice". The Journal of Pharmacology and Experimental Therapeutics 318 (1): 173–85. July 2006. doi:10.1124/jpet.106.102046. PMID 16608916. 
  25. ↑ "Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor". Bioorganic & Medicinal Chemistry Letters 15 (19): 4354–8. October 2005. doi:10.1016/j.bmcl.2005.06.062. PMID 16046122. 
  26. ↑ "Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2- trifluoroethylsulfonyl)pyrid-3-ylmethylamine". Journal of Medicinal Chemistry 46 (15): 3189–92. July 2003. doi:10.1021/jm034015u. PMID 12852748. 
  27. ↑ "Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s)". Psychopharmacology 179 (1): 271–83. April 2005. doi:10.1007/s00213-004-2099-9. PMID 15717213. 
  28. ↑ "Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2". Molecular Pharmacology 64 (4): 798–810. October 2003. doi:10.1124/mol.64.4.798. PMID 14500736. 
  29. ↑ "SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide". Bioorganic & Medicinal Chemistry Letters 14 (12): 3099–102. June 2004. doi:10.1016/j.bmcl.2004.04.017. PMID 15149652. 
  30. ↑ "Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor". Journal of Medicinal Chemistry 47 (18): 4595–9. August 2004. doi:10.1021/jm040088h. PMID 15317469. 
  31. ↑ "Investigation on quantitative structure activity relationships and pharmacophore modeling of a series of mGluR2 antagonists". International Journal of Molecular Sciences 12 (9): 5999–6023. 2011. doi:10.3390/ijms12095999. PMID 22016641. 
  32. ↑ "A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors". The Journal of Pharmacology and Experimental Therapeutics 322 (1): 254–64. July 2007. doi:10.1124/jpet.106.117093. PMID 17416742. 
  33. ↑ "Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression". Journal of Neurogenetics 25 (4): 152–66. December 2011. doi:10.3109/01677063.2011.627485. PMID 22091727. 
  34. ↑ "Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia". Science Signaling 9 (410): ra5. January 2016. doi:10.1126/scisignal.aab0467. PMID 26758213. 
  35. ↑ "Cross-signaling in metabotropic glutamate 2 and serotonin 2A receptor heteromers in mammalian cells". Pflügers Archiv 468 (5): 775–93. May 2016. doi:10.1007/s00424-015-1780-7. PMID 26780666. 
  36. ↑ "Metabotropic glutamate receptor subtype 2 is a cellular receptor for rabies virus". PLOS Pathogens 14 (7): e1007189. July 2018. doi:10.1371/journal.ppat.1007189. PMID 30028877. 

External links

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




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