Metabotropic glutamate receptor 3 explained

Metabotropic glutamate receptor 3 (mGluR3) is an inhibitory G_i/G₀-coupled G-protein coupled receptor (GPCR)^[1] generally localized to presynaptic sites of neurons in classical circuits.^[2] However, in higher cortical circuits in primates, mGluR3 are localized post-synaptically, where they strengthen rather than weaken synaptic connectivity.^[3] In humans, mGluR3 is encoded by the GRM3 gene.^{[4] [5]} Deficits in mGluR3 signaling have been linked to impaired cognition in humans,^[6] and to increased risk of schizophrenia,^[7] consistent with their expanding role in cortical evolution.

Structure

In humans, mGluR3 is encoded by the GRM3 gene on chromosome 7. At least five protein-coding isoforms are predicted based on genomic information. The mGluR3 protein is a seven-pass transmembrane protein.

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.^[5]

Clinical significance

The mGluR3 receptor encoded by the GRM3 gene has been found to be associated with a range of psychiatric disorders, including bipolar affective disorder^[8] as well as schizophrenia.^[9]

A mutation in the Kozak sequence in the 1st exon of the GRM3 gene was shown to change translation and transcription of cloned GRM3 gene constructs and was significantly associated with bipolar disorder with an odds ratio of 4.4. Subsequently, a marker in GRM3 was implicated in a large genome-wide association study of schizophrenia with statistical significance of p<10⁻⁹.^[10] A follow-up study of the Kozak sequence variant showed that it was associated with increased risk of bipolar disorder, schizophrenia and alcoholism.^[11] The mGluR3 receptor encoded by GRM3 is targetable by several drugs that have been used in previous trials of schizophrenia and anxiety disorder. The agonist, antagonist and allosteric modulator drugs of mGluR3 can now be explored as new treatments for mental illness. Other scientific evidence has been published which shows that the well established anti-manic drug lithium carbonate also changes GRM3 gene expression in the mouse brain after treatment with lithium carbonate.^[12]

Ligands

mGluR3 modulators that are significantly selective over the isoform mGluR2 are known since 2013.

Agonists

• with a bicyclo[3.1.0]hexane skeleton
  • MGS-0028^[13]
  • LY404040^[14]
  • LY379268^[15]
  • LY354740

^[16] its (+)-C4α-methyl analog is a GluR2 agonist / GluR3 antagonist^[17]

• • LY-2794193^[18]
• (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid^[19]

Antagonists

• CECXG – 38x selectivity for mGlu₃ over mGlu₂
• LY-341,495 and its 1-fluoro analog:^[20] potent orthosteric antagonists
• MGS-0039,^[21] HYDIA^[22] (both with bicyclo[3.1.0]hexane skeleton)

Allosteric modulators

• D₃-ML337: selective NAM, IC50 = 450 nM for mGluR3, IC50 >30μM for mGluR2^[23]
• MNI-137:^[24] inhibitor
• VU-0650786: NAM^[25]
• compound 7p:^[26] non-competitive antagonist (presumably allosteric inhibitor)
• LY 2389575: negative allosteric modulator.^[27]

Interactions

Metabotropic glutamate receptor 3 has been shown to interact with:

• GRIP1,^[28]
• PICK1,^[28] and
• PPM1A.^[29]

See also

• Metabotropic glutamate receptor

Further reading

• Makoff A, Volpe F, Lelchuk R, Harrington K, Emson P . Molecular characterization and localization of human metabotropic glutamate receptor type 3 . Brain Research. Molecular Brain Research . 40 . 1 . 55–63 . August 1996 . 8840013 . 10.1016/0169-328X(96)00037-X .
• Emile L, Mercken L, Apiou F, Pradier L, Bock MD, Menager J, Clot J, Doble A, Blanchard JC . 6 . Molecular cloning, functional expression, pharmacological characterization and chromosomal localization of the human metabotropic glutamate receptor type 3 . Neuropharmacology . 35 . 5 . 523–30 . May 1996 . 8887960 . 10.1016/0028-3908(96)84622-3 . 12697831 .
• Corti C, Sala CF, Yang F, Corsi M, Xuereb JH, Ferraguti F . Genomic organization of the human metabotropic glutamate receptor subtype 3 . Journal of Neurogenetics . 14 . 4 . 207–25, 271 . December 2000 . 11342382 . 10.3109/01677060009084499 . 44398182 .
• Corti C, Xuereb JH, Corsi M, Ferraguti F . Identification and characterization of the promoter region of the GRM3 gene . Biochemical and Biophysical Research Communications . 286 . 2 . 381–7 . August 2001 . 11500049 . 10.1006/bbrc.2001.5391 .
• Tomiyama M, Kimura T, Maeda T, Tanaka H, Furusawa K, Kurahashi K, Matsunaga M . Expression of metabotropic glutamate receptor mRNAs in the human spinal cord: implications for selective vulnerability of spinal motor neurons in amyotrophic lateral sclerosis . Journal of the Neurological Sciences . 189 . 1–2 . 65–9 . August 2001 . 11535235 . 10.1016/S0022-510X(01)00561-5 . 34762564 .
• Rosemond E, Peltekova V, Naples M, Thøgersen H, Hampson DR . Molecular determinants of high affinity binding to group III metabotropic glutamate receptors . The Journal of Biological Chemistry . 277 . 9 . 7333–40 . March 2002 . 11744707 . 10.1074/jbc.M110476200 . free .
• Martí SB, Cichon S, Propping P, Nöthen M . Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population . American Journal of Medical Genetics . 114 . 1 . 46–50 . January 2002 . 11840505 . 10.1002/ajmg.1624 . Peter Propping .
• Kitano J, Kimura K, Yamazaki Y, Soda T, Shigemoto R, Nakajima Y, Nakanishi S . Tamalin, a PDZ domain-containing protein, links a protein complex formation of group 1 metabotropic glutamate receptors and the guanine nucleotide exchange factor cytohesins . The Journal of Neuroscience . 22 . 4 . 1280–9 . February 2002 . 11850456 . 6757580 . 10.1523/JNEUROSCI.22-04-01280.2002 .
• 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 . 15221–4 . May 2002 . 11891216 . 10.1074/jbc.C200112200 . free . 2262/89271 . free .
• Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y . 6 . Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia . Psychiatric Genetics . 13 . 2 . 71–6 . June 2003 . 12782962 . 10.1097/01.ypg.0000056682.82896.b0 . 22535773 .
• Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, Troost D . 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 . May 2003 . 12786977 . 10.1046/j.1460-9568.2003.02657.x . 23408003 .
• Flajolet M, Rakhilin S, Wang H, Starkova N, Nuangchamnong N, Nairn AC, Greengard P . Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3 . Proceedings of the National Academy of Sciences of the United States of America . 100 . 26 . 16006–11 . December 2003 . 14663150 . 307683 . 10.1073/pnas.2136600100 . 2003PNAS..10016006F . free .
• Yao Y, Koo JC, Wells JW, Hampson DR . Expression of a truncated secreted form of the mGluR3 subtype of metabotropic glutamate receptor . Biochemical and Biophysical Research Communications . 319 . 2 . 622–8 . June 2004 . 15178451 . 10.1016/j.bbrc.2004.05.032 .
• Tang FR, Chia SC, Chen PM, Gao H, Lee WL, Yeo TS, Burgunder JM, Probst A, Sim MK, Ling EA . 6 . Metabotropic glutamate receptor 2/3 in the hippocampus of patients with mesial temporal lobe epilepsy, and of rats and mice after pilocarpine-induced status epilepticus . Epilepsy Research . 59 . 2–3 . 167–80 . 2004 . 15246118 . 10.1016/j.eplepsyres.2004.04.002 . 6205182 .
• Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR, Mattay VS, Bertolino A, Hyde TM, Shannon-Weickert C, Akil M, Crook J, Vakkalanka RK, Balkissoon R, Gibbs RA, Kleinman JE, Weinberger DR . 6 . Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia . Proceedings of the National Academy of Sciences of the United States of America . 101 . 34 . 12604–9 . August 2004 . 15310849 . 515104 . 10.1073/pnas.0405077101 . 2004PNAS..10112604E . free .

External links

• Web site: Metabotropic Glutamate Receptors: mGlu₃ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-05 . 2014-08-08 . https://web.archive.org/web/20140808050638/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2272 . dead .

Notes and References

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4. 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 . 230–3 . January 1996 . 8824806 . 10.1006/geno.1996.0036 . free .
5. Web site: Entrez Gene: GRM3 glutamate receptor, metabotropic 3.
6. Zink CF, Barker PB, Sawa A, Weinberger DR, Wang M, Quillian H, Ulrich WS, Chen Q, Jaffe AE, Kleinman JE, Hyde TM, Prettyman GE, Giegerich M, Carta K, van Ginkel M, Bigos KL . Association of Missense Mutation in FOLH1 With Decreased NAAG Levels and Impaired Working Memory Circuitry and Cognition . The American Journal of Psychiatry . 177 . 12 . 1129–1139 . December 2020 . 33256444 . 10.1176/appi.ajp.2020.19111152 . 227243375 .
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29. Flajolet M, Rakhilin S, Wang H, Starkova N, Nuangchamnong N, Nairn AC, Greengard P . Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3 . Proceedings of the National Academy of Sciences of the United States of America . 100 . 26 . 16006–11 . December 2003 . 14663150 . 307683 . 10.1073/pnas.2136600100 . 2003PNAS..10016006F . free .