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GRM5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3LMK, 4OO9, 5CGC, 5CGD
Identifiers
Aliases	GRM5, GPRC1E, MGLUR5, PPP1R86, mGlu5, glutamate metabotropic receptor 5
External IDs	OMIM: 604102; MGI: 1351342; HomoloGene: 37354; GeneCards: GRM5; OMA:GRM5 - orthologs
Gene location (Human) Chr. Chromosome 11 (human) Band 11q14.2-q14.3 Start 88,504,576 bp End 89,065,982 bp
Gene location (Mouse) Chr. Chromosome 7 (mouse) Band 7|7 D3 Start 87,233,376 bp End 87,784,115 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell buccal mucosa cell Brodmann area 10 Brodmann area 46 postcentral gyrus orbitofrontal cortex Brodmann area 23 superior frontal gyrus Region I of hippocampus proper frontal pole Top expressed in lateral septal nucleus olfactory tubercle nucleus accumbens subiculum Amygdala anterior amygdaloid area lumbar subsegment of spinal cord globus pallidus subdivision of hippocampus Region I of hippocampus proper More reference expression data BioGPS More reference expression data
Gene ontology Molecular function glutamate receptor activity G protein-coupled receptor activity signal transducer activity G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration protein binding protein tyrosine kinase activator activity protein tyrosine kinase binding Cellular component cytoplasm integral component of membrane neuron projection plasma membrane integral component of plasma membrane extracellular exosome postsynaptic density membrane presynaptic membrane Schaffer collateral - CA1 synapse postsynaptic density membrane Biological process phospholipase C-activating G protein-coupled glutamate receptor signaling pathway G protein-coupled glutamate receptor signaling pathway G protein-coupled receptor signaling pathway regulation of long-term neuronal synaptic plasticity learning cognition locomotory behavior signal transduction chemical synaptic transmission regulation of synaptic transmission, glutamatergic adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway regulation of postsynaptic membrane potential regulation of postsynaptic cytosolic calcium ion concentration regulation of protein phosphorylation regulation of translation regulation of translational elongation learning or memory calcium-mediated signaling using intracellular calcium source synapse organization positive regulation of protein tyrosine kinase activity postsynaptic modulation of chemical synaptic transmission trans-synaptic signaling by endocannabinoid, modulating synaptic transmission regulation of intracellular calcium activated chloride channel activity cellular response to amyloid-beta Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 7: 87.23 – 87.78 Mb PubMed search
Wikidata
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Metabotropic glutamate receptor 5 is an excitatory G_q-coupled G protein-coupled receptor predominantly expressed on the postsynaptic sites of neurons. In humans, it is encoded by the GRM5 gene.

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.

There has been extensive research into the role of mGluR5 in psychological disorders, such as addiction and anxiety. 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. A respectable number of potent and selective mGluR5 ligands, which also comprise PET radiotracers, has been developed to date. 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 effects in animal studies and their relatively benign safety profile. 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. The clinical use of these drugs may be limited by side effects such as amnesia and psychotomimetic symptoms, but these could be an advantage for some indications, or conversely mGluR5 positive modulators may have nootropic effects.

Agonists

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

Antagonists

• Lithium
• LY-344,545
• Mavoglurant
• Remeglurant
• SIB-1893
• (RS)-MCPG

Positive allosteric modulators

• ADX-47273
• CPPHA
• VU-29: K_i = 244 nM, EC₅₀ = 9.0 nM; VU-36: K_i = 95 nM, EC₅₀ = 10.6 nM
• VU-1545: K_i = 156 nM, EC₅₀ = 9.6 nM
• CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide)
• DFB (1-(3-fluorophenyl)-N-((3-fluorophenyl)methylideneamino)methanimine)

Negative allosteric modulators

• AZD9272
• Basimglurant
• Dipraglurant
• Fenobam
• GRN-529
• MPEP
• MTEP: more potent than MPEP
• Raseglurant
• VU0424238 (Tamagnan's name)
• GET73 (Fluvoxamine/Zafuleptine) type analog used to treat anxiety and alcoholism.

mGluR5 and addiction

Mice with a knocked out mGluR5 show a lack of cocaine self-administration regardless of dose. 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. 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

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Further reading

• Minakami R, Katsuki F, Sugiyama H (July 1993). "A variant of metabotropic glutamate receptor subtype 5: an evolutionally conserved insertion with no termination codon". Biochemical and Biophysical Research Communications. 194 (2): 622–7. doi:10.1006/bbrc.1993.1866. PMID 7688218.
• Daggett LP, Sacaan AI, Akong M, Rao SP, Hess SD, Liaw C, et al. (August 1995). "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. S2CID 12710570.
• Brakeman PR, Lanahan AA, O'Brien R, Roche K, Barnes CA, Huganir RL, et al. (March 1997). "Homer: a protein that selectively binds metabotropic glutamate receptors". Nature. 386 (6622): 284–8. Bibcode:1997Natur.386..284B. doi:10.1038/386284a0. PMID 9069287. S2CID 4346579.
• Minakami R, Jinnai N, Sugiyama H (August 1997). "Phosphorylation and calmodulin binding of the metabotropic glutamate receptor subtype 5 (mGluR5) are antagonistic in vitro". The Journal of Biological Chemistry. 272 (32): 20291–8. doi:10.1074/jbc.272.32.20291. PMID 9242710.
• Snow BE, Hall RA, Krumins AM, Brothers GM, Bouchard D, Brothers CA, et al. (July 1998). "GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain". The Journal of Biological Chemistry. 273 (28): 17749–55. doi:10.1074/jbc.273.28.17749. PMID 9651375.
• Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder CD, et al. (October 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. S2CID 16431031.
• Enz R (March 2002). "The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7". FEBS Letters. 514 (2–3): 184–8. Bibcode:2002FEBSL.514..184E. doi:10.1016/S0014-5793(02)02361-X. PMID 11943148. S2CID 44474808.
• Saugstad JA, Yang S, Pohl J, Hall RA, Conn PJ (March 2002). "Interaction between metabotropic glutamate receptor 7 and alpha tubulin". Journal of Neurochemistry. 80 (6): 980–8. doi:10.1046/j.0022-3042.2002.00778.x. PMC 2925652. PMID 11953448.
• Nash MS, Schell MJ, Atkinson PJ, Johnston NR, Nahorski SR, Challiss RA (September 2002). "Determinants of metabotropic glutamate receptor-5-mediated Ca2+ and inositol 1,4,5-trisphosphate oscillation frequency. Receptor density versus agonist concentration". The Journal of Biological Chemistry. 277 (39): 35947–60. doi:10.1074/jbc.M205622200. PMID 12119301.
• Bates B, Xie Y, Taylor N, Johnson J, Wu L, Kwak S, et al. (December 2002). "Characterization of mGluR5R, a novel, metabotropic glutamate receptor 5-related gene". Brain Research. Molecular Brain Research. 109 (1–2): 18–33. doi:10.1016/S0169-328X(02)00458-8. PMID 12531512.
• Malherbe P, Kew JN, Richards JG, Knoflach F, Kratzeisen C, Zenner MT, et al. (December 2002). "Identification and characterization of a novel splice variant of the metabotropic glutamate receptor 5 gene in human hippocampus and cerebellum". Brain Research. Molecular Brain Research. 109 (1–2): 168–78. doi:10.1016/S0169-328X(02)00557-0. PMID 12531526.
• O'Malley KL, Jong YJ, Gonchar Y, Burkhalter A, Romano C (July 2003). "Activation of metabotropic glutamate receptor mGlu5 on nuclear membranes mediates intranuclear Ca2+ changes in heterologous cell types and neurons". The Journal of Biological Chemistry. 278 (30): 28210–9. doi:10.1074/jbc.M300792200. PMID 12736269.
• Corti C, Clarkson RW, Crepaldi L, Sala CF, Xuereb JH, Ferraguti F (August 2003). "Gene structure of the human metabotropic glutamate receptor 5 and functional analysis of its multiple promoters in neuroblastoma and astroglioma cells". The Journal of Biological Chemistry. 278 (35): 33105–19. doi:10.1074/jbc.M212380200. hdl:11380/1345266. PMID 12783878.
• Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, et al. (May 2003). "Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins". The European Journal of Neuroscience. 17 (10): 2106–18. doi:10.1046/j.1460-9568.2003.02657.x. PMID 12786977. S2CID 23408003.
• Uchino M, Sakai N, Kashiwagi K, Shirai Y, Shinohara Y, Hirose K, et al. (January 2004). "Isoform-specific phosphorylation of metabotropic glutamate receptor 5 by protein kinase C (PKC) blocks Ca2+ oscillation and oscillatory translocation of Ca2+-dependent PKC". The Journal of Biological Chemistry. 279 (3): 2254–61. doi:10.1074/jbc.M309894200. PMID 14561742.
• Anneser JM, Ince PG, Shaw PJ, Borasio GD (February 2004). "Differential expression of mGluR5 in human lumbosacral motoneurons". NeuroReport. 15 (2): 271–3. doi:10.1097/00001756-200402090-00012. PMID 15076751. S2CID 31001609.
• Pacheco R, Ciruela F, Casadó V, Mallol J, Gallart T, Lluis C, et al. (August 2004). "Group I metabotropic glutamate receptors mediate a dual role of glutamate in T cell activation". The Journal of Biological Chemistry. 279 (32): 33352–8. doi:10.1074/jbc.M401761200. hdl:2445/176929. PMID 15184389.
• Kim CH, Braud S, Isaac JT, Roche KW (July 2005). "Protein kinase C phosphorylation of the metabotropic glutamate receptor mGluR5 on Serine 839 regulates Ca2+ oscillations". The Journal of Biological Chemistry. 280 (27): 25409–15. doi:10.1074/jbc.M502644200. PMID 15894802.
• Cabello N, Remelli R, Canela L, Soriguera A, Mallol J, Canela EI, et al. (April 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". The Journal of Biological Chemistry. 282 (16): 12143–53. doi:10.1074/jbc.M608880200. hdl:2445/122383. PMID 17311919.

External links

• "Metabotropic Glutamate Receptors: mGlu₅". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

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

• Genes on human chromosome 11
• Metabotropic glutamate receptors