Metabotropic glutamate receptor 7 explained

Metabotropic glutamate receptor 7 is a protein that in humans is encoded by the GRM7 gene.^{[1] [2] [3]}

Function

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 pharmacologic 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.^[3]

Glutamate has lower affinity for mGluR7 than the other metabotropic glutamate receptors and it has been suggested that mGluR7 may have a regulatory role to dampen the effects of excessive glutamate levels.^[4]

Ligands

Agonists

• AMN082

allosteric agonist;^{[5] [6]} induces rapid internalization;^[7] non-glutamatergic binding component^[6]

• LSP2-9166: mixed agonist at mGluR₄ and mGluR₇

Antagonists

• MMPIP: allosteric antagonist/inverse agonist^[8]
• XAP044

Negative allosteric modulators

• ADX71743^[9]

Interactions

Metabotropic glutamate receptor 7 has been shown to interact with PICK1.^[10]

Clinical

Mutations in both copies have been associated with developmental and epileptic encephalopathy, microcephaly, hypomyelination and cerebral atrophy.^[11]

Further reading

• Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC . Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q . Genomics . 31 . 2 . 230–233 . January 1996 . 8824806 . 10.1006/geno.1996.0036 . free .
• Flor PJ, Van Der Putten H, Rüegg D, Lukic S, Leonhardt T, Bence M, Sansig G, Knöpfel T, Kuhn R . 6 . A novel splice variant of a metabotropic glutamate receptor, human mGluR7b . Neuropharmacology . 36 . 2 . 153–159 . February 1997 . 9144652 . 10.1016/S0028-3908(96)00176-1 . 27492811 .
• Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR, Johnson BG, Schoepp DD, Belagaje RM . 6 . Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells . Brain Research. Molecular Brain Research . 53 . 1–2 . 88–97 . January 1998 . 9473604 . 10.1016/S0169-328X(97)00277-5 .
• Nakajima Y, Yamamoto T, Nakayama T, Nakanishi S . A relationship between protein kinase C phosphorylation and calmodulin binding to the metabotropic glutamate receptor subtype 7 . The Journal of Biological Chemistry . 274 . 39 . 27573–27577 . September 1999 . 10488094 . 10.1074/jbc.274.39.27573 . free .
• O'Connor V, El Far O, Bofill-Cardona E, Nanoff C, Freissmuth M, Karschin A, Airas JM, Betz H, Boehm S . 6 . Calmodulin dependence of presynaptic metabotropic glutamate receptor signaling . Science . 286 . 5442 . 1180–1184 . November 1999 . 10550060 . 10.1126/science.286.5442.1180 . free . 11858/00-001M-0000-0012-FB4D-F .
• Barbon A, Ferraboli S, Barlati S . Assignment of the human metabotropic glutamate receptor gene GRM7 to chromosome 3p26.1→p25.2 by radiation hybrid mapping . Cytogenetics and Cell Genetics . 88 . 3–4 . 288 . 2000 . 10828612 . 10.1159/000015541 . 202654909 .
• Dev KK, Nakajima Y, Kitano J, Braithwaite SP, Henley JM, Nakanishi S . PICK1 interacts with and regulates PKC phosphorylation of mGLUR7 . The Journal of Neuroscience . 20 . 19 . 7252–7257 . October 2000 . 11007882 . 6772771 . 10.1523/JNEUROSCI.20-19-07252.2000 . free .
• Bolonna AA, Kerwin RW, Munro J, Arranz MJ, Makoff AJ . Polymorphisms in the genes for mGluR types 7 and 8: association studies with schizophrenia . Schizophrenia Research . 47 . 1 . 99–103 . January 2001 . 11163549 . 10.1016/S0920-9964(99)00235-2 . 40047571 .
• Hirbec H, Perestenko O, Nishimune A, Meyer G, Nakanishi S, Henley JM, Dev KK . The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs . The Journal of Biological Chemistry . 277 . 18 . 15221–15224 . May 2002 . 11891216 . 10.1074/jbc.C200112200 . free . 2262/89271 . free .
• Enz R . The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7 . FEBS Letters . 514 . 2–3 . 184–188 . March 2002 . 11943148 . 10.1016/S0014-5793(02)02361-X . 44474808 .
• Saugstad JA, Yang S, Pohl J, Hall RA, Conn PJ . Interaction between metabotropic glutamate receptor 7 and alpha tubulin . Journal of Neurochemistry . 80 . 6 . 980–988 . March 2002 . 11953448 . 2925652 . 10.1046/j.0022-3042.2002.00778.x .
• Schulz HL, Stohr H, Weber BH . Characterization of three novel isoforms of the metabotrobic glutamate receptor 7 (GRM7) . Neuroscience Letters . 326 . 1 . 37–40 . June 2002 . 12052533 . 10.1016/S0304-3940(02)00306-3 . 32389200 .
• Kobayashi Y, Akiyoshi J, Kanehisa M, Ichioka S, Tanaka Y, Tsuru J, Hanada H, Kodama K, Isogawa K, Tsutsumi T . 6 . Lack of polymorphism in genes encoding mGluR 7, mGluR 8, GABA(A) receptor alfa-6 subunit and nociceptin/orphanin FQ receptor and panic disorder . Psychiatric Genetics . 17 . 1 . 9 . February 2007 . 17167337 . 10.1097/YPG.0b013e32801118bc .

Notes and References

1. Okamoto N, Hori S, Akazawa C, Hayashi Y, Shigemoto R, Mizuno N, Nakanishi S . Molecular characterization of a new metabotropic glutamate receptor mGluR7 coupled to inhibitory cyclic AMP signal transduction . The Journal of Biological Chemistry . 269 . 2 . 1231–1236 . January 1994 . 8288585 . 10.1016/S0021-9258(17)42247-2 . free . 2433/182290 . free .
2. Makoff A, Pilling C, Harrington K, Emson P . Human metabotropic glutamate receptor type 7: molecular cloning and mRNA distribution in the CNS . Brain Research. Molecular Brain Research . 40 . 1 . 165–170 . August 1996 . 8840028 . 10.1016/0169-328X(96)00110-6 .
3. Web site: Entrez Gene: GRM7 glutamate receptor, metabotropic 7.
4. Fisher NM, Seto M, Lindsley CW, Niswender CM . Metabotropic Glutamate Receptor 7: A New Therapeutic Target in Neurodevelopmental Disorders . Frontiers in Molecular Neuroscience . 11 . 387 . 2018 . 30405350 . 6206046 . 10.3389/fnmol.2018.00387 . free .
5. Li X, Gardner EL, Xi ZX . The metabotropic glutamate receptor 7 (mGluR7) allosteric agonist AMN082 modulates nucleus accumbens GABA and glutamate, but not dopamine, in rats . Neuropharmacology . 54 . 3 . 542–551 . March 2008 . 18155073 . 2410088 . 10.1016/j.neuropharm.2007.11.005 .
6. Palucha A, Klak K, Branski P, van der Putten H, Flor PJ, Pilc A . Activation of the mGlu7 receptor elicits antidepressant-like effects in mice . Psychopharmacology . 194 . 4 . 555–562 . November 2007 . 17622518 . 10.1007/s00213-007-0856-2 . 22011436 .
7. Pelkey KA, Yuan X, Lavezzari G, Roche KW, McBain CJ . mGluR7 undergoes rapid internalization in response to activation by the allosteric agonist AMN082 . Neuropharmacology . 52 . 1 . 108–117 . January 2007 . 16914173 . 10.1016/j.neuropharm.2006.07.020 . 23372757 .
8. Suzuki G, Tsukamoto N, Fushiki H, Kawagishi A, Nakamura M, Kurihara H, Mitsuya M, Ohkubo M, Ohta H . 6 . In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists . The Journal of Pharmacology and Experimental Therapeutics . 323 . 1 . 147–156 . October 2007 . 17609420 . 10.1124/jpet.107.124701 . 10402176 .
9. Kalinichev M, Rouillier M, Girard F, Royer-Urios I, Bournique B, Finn T, Charvin D, Campo B, Le Poul E, Mutel V, Poli S, Neale SA, Salt TE, Lütjens R . 6 . ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: in vitro and in vivo characterization . The Journal of Pharmacology and Experimental Therapeutics . 344 . 3 . 624–636 . March 2013 . 23257312 . 10.1124/jpet.112.200915 . 5774001 .
10. Dev KK, Nakajima Y, Kitano J, Braithwaite SP, Henley JM, Nakanishi S . PICK1 interacts with and regulates PKC phosphorylation of mGLUR7 . The Journal of Neuroscience . 20 . 19 . 7252–7257 . October 2000 . 11007882 . 6772771 . 10.1523/JNEUROSCI.20-19-07252.2000 .
11. Marafi D, Mitani T, Isikay S, Hertecant J, Almannai M, Manickam K, Abou Jamra R, El-Hattab AW, Rajah J, Fatih JM, Du H, Karaca E, Bayram Y, Punetha J, Rosenfeld JA, Jhangiani SN, Boerwinkle E, Akdemir ZC, Erdin S, Hunter JV, Gibbs RA, Pehlivan D, Posey JE, Lupski JR . 6 . Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy . Annals of Clinical and Translational Neurology . 7 . 5 . 610–627 . May 2020 . 32286009 . 7261753 . 10.1002/acn3.51003 .