mGlu<sub>3</sub> receptor | Metabotropic glutamate receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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mGlu3 receptor

Target not currently curated in GtoImmuPdb

Target id: 291

Nomenclature: mGlu3 receptor

Family: Metabotropic glutamate receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
class C G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 877 7q21.1-q21.2 GRM3 glutamate metabotropic receptor 3 6,17,25
Mouse 7 879 5 A1-h Grm3 glutamate receptor, metabotropic 3 12
Rat 7 879 4q32 Grm3 glutamate metabotropic receptor 3 29
Previous and Unofficial Names
mGluR3 | GPRC1C | glutamate receptor
Database Links
Specialist databases
GPCRDB grm3_human (Hs), grm3_mouse (Mm), grm3_rat (Rn)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of Metabotropic glutamate receptor 3 precursor in presence of LY341495 antagonist.
PDB Id:  3SM9
Ligand:  LY341495
Resolution:  2.26Å
Species:  Human
References:  32
Natural/Endogenous Ligands
L-glutamic acid
Comments: Other endogenous ligands include L-aspartic acid, L-serine-O-phosphate, NAAG and L-cysteine sulphinic acid

Download all structure-activity data for this target as a CSV file

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]LY341495 Rn Full agonist 7.3 pKd 26
pKd 7.3 [26]
eglumegad Hs Full agonist 8.9 pKi 9
pKi 8.9 [9]
L-CCG-I Hs Full agonist 7.4 pKi 9
pKi 7.4 [9]
L-glutamic acid Hs Full agonist 7.4 pKi 9
pKi 7.4 [9]
eglumegad Rn Full agonist 7.3 pKi 26
pKi 7.3 [26]
DCG-IV Hs Full agonist 7.2 pKi 9
pKi 7.2 [9]
DCG-IV Rn Full agonist 6.8 pKi 26
pKi 6.8 [26]
L-CCG-I Rn Full agonist 6.5 pKi 26
pKi 6.5 [26]
L-glutamic acid Rn Full agonist 6.4 pKi 26
pKi 6.4 [26]
(2R,3R)-APDC Hs Full agonist 5.3 pKi 9
pKi 5.3 [9]
(1S,3R)-ACPD Rn Full agonist 4.8 pKi 26
pKi 4.8 [26]
LY379268 Hs Full agonist 4.8 pKi 16
pKi 4.8 [16]
(1S,3R)-ACPD Hs Full agonist 4.7 pKi 9
pKi 4.7 [9]
NAAG Hs Full agonist 4.7 pKi 26
pKi 4.7 [26]
L-glutamic acid Hs Agonist 5.3 – 5.4 pEC50 22
pEC50 5.3 – 5.4 [22]
View species-specific agonist tables
Agonist Comments
Affinities listed are from displacement of antagonist ([3H]LY341495) or agonist ([3H]LY354740) for the low and high values listed, respectively, in homogenates from mGlu3-expressing recombinant cell lines. Potency in functional assays can be found in the review article [25]. To date, no ligands have shown a difference in their affinity for rat or human mGlu3 receptors. Several of the above agonists are Group II mGlu (mGlu2/3) receptor selective verses the Group I and III receptors, with the exceptions of glutamate, and (1S,3R)-ACPD. The agonist binding site for mGlu3 has been studied by homology modeling and mutagenesis [15,34].
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]LY341495 Hs Antagonist 9.1 pKd 9
pKd 9.1 [9]
LY341495 Hs Antagonist 8.9 pKi 9
pKi 8.9 [9]
MGS0039 Rn Antagonist 8.3 – 8.4 pKi 4,18
pKi 8.3 – 8.4 [4,18]
LY341495 Rn Antagonist 8.0 pKi 26
pKi 8.0 [26]
eGlu Rn Antagonist 5.4 pKi 26
pKi 5.4 [26]
(+)-MCPG Hs Antagonist 3.8 pKi 9
pKi 3.8 [9]
View species-specific antagonist tables
Antagonist Comments
Affinities listed are from displacement of antagonist ([3H]LY341495) and/or agonist ([3H]LY354740) in homogenates of mGlu3-expressing recombinant cell lines. Potency in functional assays can be found in the review article 7. To date, no ligands have shown a difference in their affinity for rat or human mGlu3 receptors.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MNI-135 Rn Negative 7.5 pEC50 8
pEC50 7.5 (EC50 3.02x10-8 M) [8]
compound 3 [PMID: 21105727] Hs Positive 5.1 pEC50 24
pEC50 5.1 (EC50 8.9x10-6 M) [24]
compound 4 [PMID: 21105727] Hs Positive 5.0 pEC50 24
pEC50 5.0 (EC50 1.04x10-5 M) [24]
compound 2 [PMID: 21105727] Hs Positive 4.9 pEC50 24
pEC50 4.9 (EC50 1.34x10-5 M) [24]
Ro4491533 Rn Negative >8.0 pIC50 33
pIC50 >8.0 (IC50 <1x10-8 M) [33]
MNI-136 Rn Negative 7.7 pIC50 8
pIC50 7.7 (IC50 2.13x10-8 M) [8]
MNI-137 Rn Negative 7.7 pIC50 8
pIC50 7.7 (IC50 2.03x10-8 M) [8]
LY2389575 Hs Negative 6.7 pIC50 27
pIC50 6.7 (IC50 1.9x10-7 M) [27]
Description: Assessed in AV-12 cells expressing the human mGlu3, activated by glutamate as agonist.
Ro4491533 Hs Negative 6.6 pIC50 3
pIC50 6.6 (IC50 2.7x10-7 M) [3]
VU0650786 Hs Negative 6.4 pIC50 7
pIC50 6.4 [7]
ML337 Rn Negative 6.2 pIC50 31
pIC50 6.2 (IC50 5.93x10-7 M) [31]
VU0463597 Rn Negative 5.8 – 6.2 pIC50 27
pIC50 5.8 – 6.2 (IC50 1.5x10-6 – 6.6x10-7 M) [27]
View species-specific allosteric modulator tables
Allosteric Modulator Comments
Targeting the allosteric site of the mGlu3 receptor is being pursued for the development of selective compounds, especially vs. mGlu2, as orthosteric ligands have so far failed to provide sufficient selectivity. Of particular interest is the development of mGlu3 selective PAMs as potential leads for neurodegenerative diseases, and NAMs which are suggested to offer potential for the treatment of schizophrenia, depression or chronic pain.
MNI-135, MNI-136, and MNI-137 [8], and Compounds 2, 3 and 4 are also mGlu2 NAMs [24]. ML289 (VU0463597) is >10 µM potency vs. rat mGlu2.
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Potassium channel
Calcium channel
Comments:  Protein Kinase A, and L-type calcium channels
References:  35
Tissue Distribution
In the human brain mGlu3 receptors are mainly localised in neurones.
Cerebellum (on the edge of the Purkinje cell layer, probably stellate cells, Golgi cells in the granule cell layer), cerebral cortex (particularly the deep layers IV-VI), hippocampus (granule cells of the dentate gyrus, caudate-putamen, reticular area of the thalamus).
Species:  Human
Technique:  Northern blotting.
References:  14
Within the brain, the mGlu3 receptor is localized both pre- and postsynaptically. It is also often found in glia and astrocytes.
Cerebral cortex, hippocampus (dentate gyrus > strata radiatum > stratum lucidum), olfactory system (anterior olfactory nucleus, olfactory tubercle, piriform cortex, nucleus of the lateral olfactory tract), basal ganglia and other subcortical regions in the forebrain (striatum and nucleus accumbens, globus pallidus > substantia nigra pars reticulata > ventral pallidum), thalamus and epithalamus, brainstem and spinal cord, cerebellum.
Species:  Mouse
Technique:  immunocytochemistry.
References:  28
Aanterior olfactory nucleus, cerebral neo- and mesocortical regions, lateral amygdaloid nucleus, ventral part of the basolateral amygdaloid nucleus, dorsal endopiriform nucleus, supraoptic nucleus, superficial layers of the superior colliculus, inferior colliculus, interpeduncular nucleus, superior olivary nuclei, and Golgi cells in the cerebellar cortex > striatum, nucleus accumbens, ventral pallidum, globus pallidus, entopeduncular nucleus, lateral hypothalamic area, hypothalamic paraventricular nucleus, medial habenular nucleus, anterior pretectal nucleus, Barrington's nucleus, Nucleus O, paragenual nucleus, trigeminal sensory complex, cochlear nuclei, dorsal motor nucleus of the trigeminal nerve, dorsal cap of the inferior olive, spinal dorsal horn, and lamina X of the spinal cord, stellate cells in the cerebellar cortex, neurons in the deep cerebellar nuclei.
Species:  Rat
Technique:  in situ hybridization.
References:  19
Islets of Langerhans and pancreatic alpha-cell and beta-cell lines.
Species:  Rat
Technique:  RT-PCR and immunoblot.
References:  2
Dorsal cochlear nucleus.
Species:  Rat
Technique:  immunocytochemistry.
References:  21
Reticular nucleus of the thalamus, rostral olfactory structures, hippocampus.
Species:  Rat
Technique:  immunocytochemistry.
References:  20
Reticular thalamic nucleus >> mediodorsal thalamic nucleus, centromedial/centrolateral thalamic nuclei, ventromedial thalamic nucleus > other thalamic nuclei.
Species:  Rat
Technique:  in situ hybridisation.
References:  13
Cerebral cortex and caudate putamen, granule cells of hippocampal dentate gyrus.
Species:  Rat
Technique:  in situ hybridization.
References:  30
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Native mGlu3 receptor function has been linked to the regulation of GABA release from the rat cortical neurons in primary culture.
Species:  Rat
Tissue:  Primary culture of cortical neurons.
Response measured:  [3H]-GABA release.
References:  35
mGlu3 receptor-mediated release of Nerve Growth factor from cultured astrocytes.
Species:  Rat
Tissue:  Secondary Glial cultures from primary rat cortical astrocytes.
Response measured:  Nerve Growth Factor release.
References:  5
Measurement of cAMP levels in CHO cells transfected with the rat mGlu3 receptor.
Species:  Rat
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP production.
References:  30
Measurement of cAMP levels in rat glutamate transporter (RGT) cells transfected with the mGlu3 receptor.
Species:  Human
Tissue:  RGT cells.
Response measured:  Inhibition of cAMP accumulation.
References:  11
Measurement of IP levels in HEK 293 cells transfected with the rat mGlu3 receptor and Gqi9.
Species:  Rat
Tissue:  HEK 293 cells.
Response measured:  IP accumulation.
References:  1
Physiological Functions
MGlu3 activation is thought to inhibit synaptic transmission.
Species:  Rat
Tissue:  Hippocampal slices.
References:  10
mGlu3 receptor activation modulates GABA release.
Species:  Rat
Tissue:  Primary cortical neuron culture.
References:  35
It is suggested that mGlu3 receptor activation may result in the release of nerve growth factor (NGF) from rat cultured cortical astrocytes.
Species:  Rat
Tissue:  Cortical astrocytes in culture.
References:  5
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Grm3tm1Ddsc Grm3tm1Ddsc/Grm3tm1Ddsc
involves: 129S1/Sv * 129X1/SvJ * CD-1
MGI:1351340  MP:0001362 abnormal anxiety-related response PMID: 15619115 
Grm3tm1Dgen Grm3tm1Dgen/Grm3tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1351340  MP:0002169 no abnormal phenotype detected
Biologically Significant Variants
Type:  Splice variants
Species:  Human
Description:  The existence of alternatively spliced isoforms of mGlu3 has recently been reported. These are truncated forms and unequivocal expression in tissue (human brain) has been demonstrated only for GRM3Δ4, which lacks the entire transmembrane domain. Although this splice form could result in a secreted protein, immunohistochemical and fractional data showed association with the plasma membrane.
References:  23
General Comments
To date, the relative lack of mGlu3 vs. mGlu2 receptor agonists/antagonists and limited results/availability of with selective antibodies has hampered efforts to differentiate the relative roles of these two highly related receptors in the Group II mGlu receptor family.


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17. Muto T, Tsuchiya D, Morikawa K, Jingami H. (2007) Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc. Natl. Acad. Sci. U.S.A., 104 (10): 3759-64. [PMID:17360426]

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24. Schann S, Mayer S, Franchet C, Frauli M, Steinberg E, Thomas M, Baron L, Neuville P. (2010) Chemical switch of a metabotropic glutamate receptor 2 silent allosteric modulator into dual metabotropic glutamate receptor 2/3 negative/positive allosteric modulators. J. Med. Chem., 53 (24): 8775-9. [PMID:21105727]

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31. Wenthur CJ, Morrison R, Felts AS, Smith KA, Engers JL, Byers FW, Daniels JS, Emmitte KA, Conn PJ, Lindsley CW. (2013) 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). J. Med. Chem., 56 (12): 5208-12. [PMID:23718281]

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