{{Short description|Mammalian protein found in humans}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}}
'''Metabotropic glutamate receptor 3''' ('''mGluR3''') is an inhibitory G<sub>i</sub>/G<sub>0</sub>-coupled G-protein coupled receptor (GPCR)<ref name="Ambrosini">{{cite journal | vauthors = Ambrosini A, Bresciani L, Fracchia S, Brunello N, Racagni G | title = Metabotropic glutamate receptors negatively coupled to adenylate cyclase inhibit N-methyl-D-aspartate receptor activity and prevent neurotoxicity in mesencephalic neurons in vitro | journal = Molecular Pharmacology | volume = 47 | issue = 5 | pages = 1057–64 | date = May 1995 | doi = 10.1016/S0026-895X(25)08596-7 | pmid = 7746273 | url = http://molpharm.aspetjournals.org/cgi/content/abstract/47/5/1057 | format = abstract | url-access = subscription }}</ref> generally localized to presynaptic sites of neurons in classical circuits.<ref name="Shigemoto">{{cite journal | vauthors = Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, Flor PJ, Neki A, Abe T, Nakanishi S, Mizuno N | title = Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus | journal = The Journal of Neuroscience | volume = 17 | issue = 19 | pages = 7503–22 | date = October 1997 | pmid = 9295396 | pmc = 6573434 | doi = 10.1523/JNEUROSCI.17-19-07503.1997 }}</ref> However, in higher cortical circuits in primates, mGluR3 are localized post-synaptically, where they strengthen rather than weaken synaptic connectivity.<ref name="Jin">{{cite journal | vauthors = Jin LE, Wang M, Galvin VC, Lightbourne TC, Conn PJ, Arnsten AF, Paspalas CD | title = mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks | journal = Cerebral Cortex | volume = 28 | issue = 3 | pages = 974–987 | date = March 2018 | pmid = 28108498 | pmc = 5974790 | doi = 10.1093/cercor/bhx005 | url = }}</ref> In humans, mGluR3 is encoded by the ''GRM3'' gene.<ref name="pmid8824806">{{cite journal | vauthors = Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC | title = Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q | journal = Genomics | volume = 31 | issue = 2 | pages = 230–3 | date = January 1996 | pmid = 8824806 | doi = 10.1006/geno.1996.0036 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: GRM3 glutamate receptor, metabotropic 3| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=2913}}</ref> Deficits in mGluR3 signaling have been linked to impaired cognition in humans,<ref name="Zink">{{cite journal | vauthors = 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 | title = Association of Missense Mutation in FOLH1 With Decreased NAAG Levels and Impaired Working Memory Circuitry and Cognition | journal = The American Journal of Psychiatry | volume = 177 | issue = 12 | pages = 1129–1139 | date = December 2020 | pmid = 33256444 | doi = 10.1176/appi.ajp.2020.19111152 | s2cid = 227243375 }}</ref> and to increased risk of schizophrenia,<ref name = "Saini_2017">{{cite journal | vauthors = Saini SM, Mancuso SG, Mostaid MS, Liu C, Pantelis C, Everall IP, Bousman CA | title = Meta-analysis supports GWAS-implicated link between GRM3 and schizophrenia risk | journal = Translational Psychiatry | volume = 7 | issue = 8 | pages = e1196 | date = August 2017 | pmid = 28786982 | pmc = 5611739 | doi = 10.1038/tp.2017.172 | doi-access = free }}</ref> 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.<ref name="entrez"/>
mGluR3 assumes an expanded role in the primate association cortex, where it supports higher cognitive functions. In rodents, mGluR3 are located primarily at presynaptic terminals, where they inhibit glutamate release.<ref>{{cite journal | vauthors = Woo E, Datta D, Arnsten AF | title = Glutamate Metabotropic Receptor Type 3 (mGlu3) Localization in the Rat Prelimbic Medial Prefrontal Cortex | journal = Frontiers in Neuroanatomy | volume = 16 | article-number = 849937 | year = 2022 | pmid = 35444520 | doi = 10.3389/fnana.2022.849937 | pmc = 9013768 | doi-access = free }}</ref> By contrast, in the primate prefrontal cortex<ref name = "Jin_2018">{{cite journal | vauthors = Jin LE, Wang M, Galvin VC, Lightbourne TC, Conn PJ, Arnsten AF, Paspalas CD | title = mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks | journal = Cerebral Cortex | volume = 28 | issue = 3 | pages = 974–987 | date = March 2018 | pmid = 28108498 | doi = 10.1093/cercor/bhx005 | pmc = 5974790 }}</ref> and entorhinal cortex,<ref>{{cite journal | vauthors = Datta D, Perone I, Morozov YM, Arellano J, Duque A, Rakic P, van Dyck CH, Arnsten AF | title = Localization of PDE4D, HCN1 channels, and mGluR3 in rhesus macaque entorhinal cortex may confer vulnerability in Alzheimer's disease | journal = Cerebral Cortex | volume = 33 | issue = 24 | pages = 11501–11516 | date = December 2023 | pmid = 37874022 | doi = 10.1093/cercor/bhad382 | pmc = 10724870 }}</ref> mGluR3 are predominantly postsynaptic, residing on dendritic spines where they regulate the cAMP-driven activation of calcium signaling.<ref name = "Jin_2018" />
Feedforward cAMP–calcium signaling can open nearby potassium channels, reducing synaptic efficacy and impairing cognition—a phenomenon termed dynamic network connectivity.<ref>{{cite journal | vauthors = Shipman SL, Nicoll RA | title = A subtype-specific function for the extracellular domain of neuroligin 1 in hippocampal LTP | journal = Neuron | volume = 76 | issue = 2 | pages = 309–316 | date = October 2012 | pmid = 23083734 | doi = 10.1016/j.neuron.2012.07.024 | pmc = 3998838 }}</ref> mGluR3 counteract this process by closing potassium channels and thereby strengthening the functional connectivity of prefrontal cortical networks. In addition to responding to glutamate, mGluR3 are also activated by N-acetylaspartylglutamic acid (NAAG), which is co-released with glutamate but selectively stimulates mGluR3.<ref>{{cite journal | vauthors = Carvalho GQ, Pereira-Santos M, Marcon LD, Louro ID, Peluzio MC, Santos DB | title = Maternal polymorphisms in the FADS1 and FADS2 genes modify the association between PUFA ingestion and plasma concentrations of omega-3 polyunsaturated fatty acids | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 150 | pages = 38–46 | date = November 2019 | pmid = 31568926 | doi = 10.1016/j.plefa.2019.09.004 }}</ref> Levels of NAAG in the cerebrospinal fluid correlate with cognitive performance.<ref>{{cite journal | vauthors = Chandra A, Alt J, Dastgheyb RM, Veenhuis RT, Rais R, Coughlin JM, Slusher BS, Rubin LH | title = Associations between cerebrospinal fluid N-acetyl-aspartyl-glutamate (NAAG) and cognitive function in people with HIV | journal = AIDS | date = September 2025 | volume = 40 | issue = 1 | pages = 58–63 | pmid = 40965153 | doi = 10.1097/QAD.0000000000004341 }}</ref> During neuroinflammation, the enzyme glutamate carboxypeptidase II (GCPII) degrades NAAG, thereby impairing prefrontal cortical cognitive function.<ref>{{cite journal | vauthors = Yang S, Datta D, Duque A, Morozov YM, Arellano J, Slusher BS, Wang M, Arnsten AF | title = Inhibition of glutamate-carboxypeptidase-II in dorsolateral prefrontal cortex: potential therapeutic target for neuroinflammatory cognitive disorders | journal = Molecular Psychiatry | volume = 27 | issue = 10 | pages = 4252–4263 | date = October 2022 | pmid = 35732693 | doi = 10.1038/s41380-022-01656-x | pmc = 9718677 }}</ref> A gain-of-function variant in the gene encoding GCPII has been linked to cognitive impairment in humans.<ref>{{cite journal | vauthors = Tao J, Chen H, Zhu L, Pan D, Fang J, Chen Y, Mao J, Shen L | title = Macular hole edge morphology predicts restoration of postoperative retinal microstructure and functional outcome | journal = BMC Ophthalmology | volume = 20 | issue = 1 | article-number = 280 | date = July 2020 | pmid = 32652958 | doi = 10.1186/s12886-020-01541-7 | pmc = 7353697 | doi-access = free }}</ref>
== 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<ref name="Kandaswamy_2013">{{cite journal | vauthors = Kandaswamy R, McQuillin A, Sharp SI, Fiorentino A, Anjorin A, Blizard RA, Curtis D, Gurling HM | title = Genetic association, mutation screening, and functional analysis of a Kozak sequence variant in the metabotropic glutamate receptor 3 gene in bipolar disorder | journal = JAMA Psychiatry | volume = 70 | issue = 6 | pages = 591–8 | date = June 2013 | pmid = 23575746 | doi = 10.1001/jamapsychiatry.2013.38 | doi-access = }}</ref> as well as schizophrenia.<ref>{{cite journal | vauthors = Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, Georgieva L, Rees E, Palta P, Ruderfer DM, Carrera N, Humphreys I, Johnson JS, Roussos P, Barker DD, Banks E, Milanova V, Grant SG, Hannon E, Rose SA, Chambert K, Mahajan M, Scolnick EM, Moran JL, Kirov G, Palotie A, McCarroll SA, Holmans P, Sklar P, Owen MJ, Purcell SM, O'Donovan MC | title = De novo mutations in schizophrenia implicate synaptic networks | journal = Nature | volume = 506 | issue = 7487 | pages = 179–84 | date = February 2014 | pmid = 24463507 | pmc = 4237002 | doi = 10.1038/nature12929 | bibcode = 2014Natur.506..179F }}</ref><ref name="Saini_2017" />
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.<ref name="Kandaswamy_2013" /> Subsequently, a marker in GRM3 was implicated in a large genome-wide association study of schizophrenia with statistical significance of p<10<sup>−9</sup>.<ref name="pmid25056061">{{cite journal | vauthors = Ripke S, Neale BM, Corvin A, Walters JT, Farh KH, Holmans PA, etal | collaboration = Schizophrenia Working Group of the Psychiatric Genomics Consortium | title = Biological insights from 108 schizophrenia-associated genetic loci | journal = Nature | volume = 511 | issue = 7510 | pages = 421–7 | date = July 2014 | pmid = 25056061 | pmc = 4112379 | doi = 10.1038/nature13595 | bibcode = 2014Natur.511..421S }}</ref> A follow-up study of the Kozak sequence variant showed that it was associated with increased risk of bipolar disorder, schizophrenia and alcoholism.<ref name="pmid25046171">{{cite journal | vauthors = O'Brien NL, Way MJ, Kandaswamy R, Fiorentino A, Sharp SI, Quadri G, Alex J, Anjorin A, Ball D, Cherian R, Dar K, Gormez A, Guerrini I, Heydtmann M, Hillman A, Lankappa S, Lydall G, O'Kane A, Patel S, Quested D, Smith I, Thomson AD, Bass NJ, Morgan MY, Curtis D, McQuillin A | title = The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder | journal = Psychiatric Genetics | volume = 24 | issue = 6 | pages = 277–8 | date = December 2014 | pmid = 25046171 | pmc = 4272221 | doi = 10.1097/YPG.0000000000000050 }}</ref> 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.<ref name="Kandaswamy_2013" /> 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.<ref name="pmid17622937">{{cite journal | vauthors = McQuillin A, Rizig M, Gurling HM | title = A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder | journal = Pharmacogenetics and Genomics | volume = 17 | issue = 8 | pages = 605–17 | date = August 2007 | pmid = 17622937 | doi = 10.1097/FPC.0b013e328011b5b2 | s2cid = 31180768 }}</ref>
==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<ref>{{cite journal | vauthors = Nakazato A, Kumagai T, Sakagami K, Yoshikawa R, Suzuki Y, Chaki S, Ito H, Taguchi T, Nakanishi S, Okuyama S | title = Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists | journal = Journal of Medicinal Chemistry | volume = 43 | issue = 25 | pages = 4893–909 | date = December 2000 | pmid = 11123999 | doi = 10.1021/jm000346k }}</ref> **LY404040<ref>{{cite journal | vauthors = Monn JA, Massey SM, Valli MJ, Henry SS, Stephenson GA, Bures M, Hérin M, Catlow J, Giera D, Wright RA, Johnson BG, Andis SL, Kingston A, Schoepp DD | title = Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors | journal = Journal of Medicinal Chemistry | volume = 50 | issue = 2 | pages = 233–40 | date = January 2007 | pmid = 17228865 | doi = 10.1021/jm060917u }}</ref> **LY379268<ref>{{cite journal | vauthors = Monn JA, Valli MJ, Massey SM, Hansen MM, Kress TJ, Wepsiec JP, Harkness AR, Grutsch JL, Wright RA, Johnson BG, Andis SL, Kingston A, Tomlinson R, Lewis R, Griffey KR, Tizzano JP, Schoepp DD | title = Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors | journal = Journal of Medicinal Chemistry | volume = 42 | issue = 6 | pages = 1027–40 | date = March 1999 | pmid = 10090786 | doi = 10.1021/jm980616n }}</ref> **LY354740;<ref>{{cite journal | vauthors = Monn JA, Valli MJ, Massey SM, Wright RA, Salhoff CR, Johnson BG, Howe T, Alt CA, Rhodes GA, Robey RL, Griffey KR, Tizzano JP, Kallman MJ, Helton DR, Schoepp DD | title = Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties | journal = Journal of Medicinal Chemistry | volume = 40 | issue = 4 | pages = 528–37 | date = February 1997 | pmid = 9046344 | doi = 10.1021/jm9606756 }}</ref> its (+)-C4α-methyl analog is a GluR2 agonist / GluR3 antagonist<ref>{{cite journal | vauthors = Dominguez C, Prieto L, Valli MJ, Massey SM, Bures M, Wright RA, Johnson BG, Andis SL, Kingston A, Schoepp DD, Monn JA | title = Methyl substitution of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate (LY354740) determines functional activity at metabotropic glutamate receptors: identification of a subtype selective mGlu2 receptor agonist | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 10 | pages = 3605–12 | date = May 2005 | pmid = 15887967 | doi = 10.1021/jm040222y }}</ref> **LY-2794193<ref name="pmid29350927">{{cite journal | vauthors = Monn JA, Henry SS, Massey SM, Clawson DK, Chen Q, Diseroad BA, Bhardwaj RM, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang XS, Carter JH, Getman BG, Adragni K, Broad LM, Sanger HE, Ursu D, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL, Hao J | title = Synthesis and Pharmacological Characterization of C4<sub>β</sub>-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu<sub>3</sub> Receptor Agonist | journal = Journal of Medicinal Chemistry | volume = 61 | issue = 6 | pages = 2303–2328 | date = March 2018 | pmid = 29350927 | doi = 10.1021/acs.jmedchem.7b01481 }}</ref> *(''R'')-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid<ref>{{cite journal | vauthors = Clausen RP, Bräuner-Osborne H, Greenwood JR, Hermit MB, Stensbøl TB, Nielsen B, Krogsgaard-Larsen P | title = Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 19 | pages = 4240–5 | date = September 2002 | pmid = 12213064 | doi = 10.1021/jm020122x }}</ref>
===Antagonists===
*CECXG – 38x selectivity for mGlu<sub>3</sub> over mGlu<sub>2</sub> *LY-341,495 and its 1-fluoro analog:<ref>{{cite journal | vauthors = Sakagami K, Yasuhara A, Chaki S, Yoshikawa R, Kawakita Y, Saito A, Taguchi T, Nakazato A | title = Synthesis, in vitro pharmacology, and pharmacokinetic profiles of 2-[1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid and its 6-heptyl ester, a potent mGluR2 antagonist | journal = Bioorganic & Medicinal Chemistry | volume = 16 | issue = 8 | pages = 4359–66 | date = April 2008 | pmid = 18348906 | doi = 10.1016/j.bmc.2008.02.066 }}</ref> potent orthosteric antagonists *MGS-0039,<ref>a) {{cite journal | vauthors = Nakazato A, Sakagami K, Yasuhara A, Ohta H, Yoshikawa R, Itoh M, Nakamura M, Chaki S | title = Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 18 | pages = 4570–87 | date = August 2004 | pmid = 15317467 | doi = 10.1021/jm0400294 }}, <br>b) {{cite journal | vauthors = Yasuhara A, Nakamura M, Sakagami K, Shimazaki T, Yoshikawa R, Chaki S, Ohta H, Nakazato A | title = Prodrugs of 3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039): a potent and orally active group II mGluR antagonist with antidepressant-like potential | journal = Bioorganic & Medicinal Chemistry | volume = 14 | issue = 12 | pages = 4193–207 | date = June 2006 | pmid = 16487713 | doi = 10.1016/j.bmc.2006.01.060 }}, <br>c) {{cite journal | vauthors = Yasuhara A, Sakagami K, Yoshikawa R, Chaki S, Nakamura M, Nakazato A | title = Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists | journal = Bioorganic & Medicinal Chemistry | volume = 14 | issue = 10 | pages = 3405–20 | date = May 2006 | pmid = 16431115 | doi = 10.1016/j.bmc.2005.12.061 }}</ref> HYDIA<ref>{{cite journal | vauthors = Woltering TJ, Adam G, Huguenin P, Wichmann J, Kolczewski S, Gatti S, Bourson A, Kew JN, Richards G, Kemp JA, Mutel V, Knoflach F | title = Asymmetric synthesis and receptor pharmacology of the group II mGlu receptor ligand (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid-HYDIA | journal = ChemMedChem | volume = 3 | issue = 2 | pages = 323–35 | date = February 2008 | pmid = 18058780 | doi = 10.1002/cmdc.200700226 | s2cid = 1695024 }}</ref> (both with bicyclo[3.1.0]hexane skeleton)
thumb|D<sub>3</sub>-ML337|255px|right
===Allosteric modulators=== *ML337: selective NAM, IC50 = 450 nM for mGluR3, IC50 >30μM for mGluR2<ref name="pmid23718281">{{cite journal | vauthors = Wenthur CJ, Morrison R, Felts AS, Smith KA, Engers JL, Byers FW, Daniels JS, Emmitte KA, Conn PJ, Lindsley CW | title = Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM) | journal = Journal of Medicinal Chemistry | volume = 56 | issue = 12 | pages = 5208–12 | date = June 2013 | pmid = 23718281 | pmc = 3769689 | doi = 10.1021/jm400439t }}</ref> *MNI-137:<ref>{{cite journal | vauthors = Hemstapat K, Da Costa H, Nong Y, Brady AE, Luo Q, Niswender CM, Tamagnan GD, Conn PJ | title = A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 322 | issue = 1 | pages = 254–64 | date = July 2007 | pmid = 17416742 | doi = 10.1124/jpet.106.117093 | s2cid = 3820477 }}</ref> inhibitor * VU-0650786: NAM<ref name="pmid28947938">{{cite journal | vauthors = Engers JL, Bollinger KA, Weiner RL, Rodriguez AL, Long MF, Breiner MM, Chang S, Bollinger SR, Bubser M, Jones CK, Morrison RD, Bridges TM, Blobaum AL, Niswender CM, Conn PJ, Emmitte KA, Lindsley CW | title = Design and Synthesis of ''N''-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu<sub>3</sub> NAMs | journal = ACS Medicinal Chemistry Letters | volume = 8 | issue = 9 | pages = 925–930 | date = September 2017 | pmid = 28947938 | pmc = 5601378 | doi = 10.1021/acsmedchemlett.7b00249 }}</ref> *compound 7p:<ref>{{cite journal | vauthors = Woltering TJ, Wichmann J, Goetschi E, Adam G, Kew JN, Knoflach F, Ballard TM, Huwyler J, Mutel V, Gatti S | title = Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 3. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 8 | pages = 2725–9 | date = April 2008 | pmid = 18374569 | doi = 10.1016/j.bmcl.2008.02.076 }}</ref> non-competitive antagonist (presumably allosteric inhibitor) * LY 2389575: negative allosteric modulator.<ref name="pmid33407565">{{cite journal | vauthors = Zinni M, Mairesse J, Pansiot J, Fazio F, Iacovelli L, Antenucci N, Orlando R, Nicoletti F, Vaiman D, Baud O | title = mGlu3 receptor regulates microglial cell reactivity in neonatal rats | journal = Journal of Neuroinflammation | volume = 18 | issue = 1 | article-number = 13 | date = January 2021 | pmid = 33407565 | pmc = 7789385 | doi = 10.1186/s12974-020-02049-z | doi-access = free }}</ref>
== Interactions ==
Metabotropic glutamate receptor 3 has been shown to interact with: * GRIP1,<ref name = pmid11891216>{{cite journal | vauthors = Hirbec H, Perestenko O, Nishimune A, Meyer G, Nakanishi S, Henley JM, Dev KK | title = The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs | journal = The Journal of Biological Chemistry | volume = 277 | issue = 18 | pages = 15221–4 | date = May 2002 | pmid = 11891216 | doi = 10.1074/jbc.C200112200 | doi-access = free | hdl = 2262/89271 | hdl-access = free }}</ref> * PICK1,<ref name = pmid11891216/> and * PPM1A.<ref name = pmid14663150>{{cite journal | vauthors = Flajolet M, Rakhilin S, Wang H, Starkova N, Nuangchamnong N, Nairn AC, Greengard P | title = Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 26 | pages = 16006–11 | date = December 2003 | pmid = 14663150 | pmc = 307683 | doi = 10.1073/pnas.2136600100 | bibcode = 2003PNAS..10016006F | doi-access = free }}</ref> *Raptin<ref>{{cite journal | vauthors = Cabot L, Fenselau H | title = Raptin, a novel brain hormone links sleep health to body weight gain | journal = Cell Research | date = February 2025 | volume = 35 | issue = 4 | pages = 231–232 | pmid = 39962190 | doi = 10.1038/s41422-025-01083-x | pmc = 11958691 }}</ref>
== See also == * Metabotropic glutamate receptor
== References == {{reflist|32em}}
== Further reading == {{refbegin|32em}} * {{cite journal | vauthors = Makoff A, Volpe F, Lelchuk R, Harrington K, Emson P | title = Molecular characterization and localization of human metabotropic glutamate receptor type 3 | journal = Brain Research. Molecular Brain Research | volume = 40 | issue = 1 | pages = 55–63 | date = August 1996 | pmid = 8840013 | doi = 10.1016/0169-328X(96)00037-X }} * {{cite journal | vauthors = Emile L, Mercken L, Apiou F, Pradier L, Bock MD, Menager J, Clot J, Doble A, Blanchard JC | title = Molecular cloning, functional expression, pharmacological characterization and chromosomal localization of the human metabotropic glutamate receptor type 3 | journal = Neuropharmacology | volume = 35 | issue = 5 | pages = 523–30 | date = May 1996 | pmid = 8887960 | doi = 10.1016/0028-3908(96)84622-3 | s2cid = 12697831 }} * {{cite journal | vauthors = Corti C, Sala CF, Yang F, Corsi M, Xuereb JH, Ferraguti F | title = Genomic organization of the human metabotropic glutamate receptor subtype 3 | journal = Journal of Neurogenetics | volume = 14 | issue = 4 | pages = 207–25, 271 | date = December 2000 | pmid = 11342382 | doi = 10.3109/01677060009084499 | s2cid = 44398182 | hdl = 11380/1345106 | hdl-access = free }} * {{cite journal | vauthors = Corti C, Xuereb JH, Corsi M, Ferraguti F | title = Identification and characterization of the promoter region of the GRM3 gene | journal = Biochemical and Biophysical Research Communications | volume = 286 | issue = 2 | pages = 381–7 | date = August 2001 | pmid = 11500049 | doi = 10.1006/bbrc.2001.5391 | bibcode = 2001BBRC..286..381C | hdl = 11380/1345246 | hdl-access = free }} * {{cite journal | vauthors = Tomiyama M, Kimura T, Maeda T, Tanaka H, Furusawa K, Kurahashi K, Matsunaga M | title = Expression of metabotropic glutamate receptor mRNAs in the human spinal cord: implications for selective vulnerability of spinal motor neurons in amyotrophic lateral sclerosis | journal = Journal of the Neurological Sciences | volume = 189 | issue = 1–2 | pages = 65–9 | date = August 2001 | pmid = 11535235 | doi = 10.1016/S0022-510X(01)00561-5 | s2cid = 34762564 }} * {{cite journal | vauthors = Rosemond E, Peltekova V, Naples M, Thøgersen H, Hampson DR | title = Molecular determinants of high affinity binding to group III metabotropic glutamate receptors | journal = The Journal of Biological Chemistry | volume = 277 | issue = 9 | pages = 7333–40 | date = March 2002 | pmid = 11744707 | doi = 10.1074/jbc.M110476200 | doi-access = free }} * {{cite journal | vauthors = Martí SB, Cichon S, Propping P, Nöthen M | title = Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population | journal = American Journal of Medical Genetics | volume = 114 | issue = 1 | pages = 46–50 | date = January 2002 | pmid = 11840505 | doi = 10.1002/ajmg.1624 | author3-link = Peter Propping }} * {{cite journal | vauthors = Kitano J, Kimura K, Yamazaki Y, Soda T, Shigemoto R, Nakajima Y, Nakanishi S | title = Tamalin, a PDZ domain-containing protein, links a protein complex formation of group 1 metabotropic glutamate receptors and the guanine nucleotide exchange factor cytohesins | journal = The Journal of Neuroscience | volume = 22 | issue = 4 | pages = 1280–9 | date = February 2002 | pmid = 11850456 | pmc = 6757580 | doi = 10.1523/JNEUROSCI.22-04-01280.2002 }} * {{cite journal | vauthors = Hirbec H, Perestenko O, Nishimune A, Meyer G, Nakanishi S, Henley JM, Dev KK | title = The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs | journal = The Journal of Biological Chemistry | volume = 277 | issue = 18 | pages = 15221–4 | date = May 2002 | pmid = 11891216 | doi = 10.1074/jbc.C200112200 | doi-access = free | hdl = 2262/89271 | hdl-access = free }} * {{cite journal | vauthors = Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y | title = Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia | journal = Psychiatric Genetics | volume = 13 | issue = 2 | pages = 71–6 | date = June 2003 | pmid = 12782962 | doi = 10.1097/01.ypg.0000056682.82896.b0 | s2cid = 22535773 }} * {{cite journal | vauthors = Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, Troost D | title = Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins | journal = The European Journal of Neuroscience | volume = 17 | issue = 10 | pages = 2106–18 | date = May 2003 | pmid = 12786977 | doi = 10.1046/j.1460-9568.2003.02657.x | s2cid = 23408003 }} * {{cite journal | vauthors = Flajolet M, Rakhilin S, Wang H, Starkova N, Nuangchamnong N, Nairn AC, Greengard P | title = Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 26 | pages = 16006–11 | date = December 2003 | pmid = 14663150 | pmc = 307683 | doi = 10.1073/pnas.2136600100 | bibcode = 2003PNAS..10016006F | doi-access = free }} * {{cite journal | vauthors = Yao Y, Koo JC, Wells JW, Hampson DR | title = Expression of a truncated secreted form of the mGluR3 subtype of metabotropic glutamate receptor | journal = Biochemical and Biophysical Research Communications | volume = 319 | issue = 2 | pages = 622–8 | date = June 2004 | pmid = 15178451 | doi = 10.1016/j.bbrc.2004.05.032 | bibcode = 2004BBRC..319..622Y }} * {{cite journal | vauthors = Tang FR, Chia SC, Chen PM, Gao H, Lee WL, Yeo TS, Burgunder JM, Probst A, Sim MK, Ling EA | title = 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 | journal = Epilepsy Research | volume = 59 | issue = 2–3 | pages = 167–80 | year = 2004 | pmid = 15246118 | doi = 10.1016/j.eplepsyres.2004.04.002 | s2cid = 6205182 | url = http://scholarbank.nus.edu.sg/handle/10635/32183 }} * {{cite journal | vauthors = 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 | title = Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 34 | pages = 12604–9 | date = August 2004 | pmid = 15310849 | pmc = 515104 | doi = 10.1073/pnas.0405077101 | bibcode = 2004PNAS..10112604E | doi-access = free }} {{refend}}
== External links == * {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2272 | title = Metabotropic Glutamate Receptors: mGlu<sub>3</sub> | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-12-05 | archive-date = 2014-08-08 | archive-url = https://web.archive.org/web/20140808050638/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2272 | url-status = dead }}
{{NLM content}} {{PDB Gallery|geneid=2913}} {{G protein-coupled receptors|g3}} {{Metabotropic glutamate receptor modulators}}
Category:Metabotropic glutamate receptors