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mGlu6 receptor

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Target not currently curated in GtoImmuPdb

Target id: 294

Nomenclature: mGlu6 receptor

Family: Metabotropic glutamate receptors

Gene and Protein Information Click here for help
class C G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 877 5q35.3 GRM6 glutamate metabotropic receptor 6 13,15
Mouse 7 871 11 B1.3 Grm6 glutamate receptor, metabotropic 6
Rat 7 871 10q22 Grm6 glutamate metabotropic receptor 6 19
Previous and Unofficial Names Click here for help
Gprc1f | mGluR6 | nob4 | nerg1 | nob2 | nob3 | glutamate receptor
Database Links Click here for help
Specialist databases
GPCRDB grm6_human (Hs), grm6_mouse (Mm), grm6_rat (Rn)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands Click here for help
L-glutamic acid
L-serine-O-phosphate
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 go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
L-AP4 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 6.7 – 7.3 pEC50 15,27
pEC50 6.7 – 7.3 [15,27]
L-serine-O-phosphate Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 6.4 pEC50 15
pEC50 6.4 [15]
L-CCG-I Small molecule or natural product Click here for species-specific activity table Hs Full agonist 6.2 pEC50 15
pEC50 6.2 [15]
LSP1-2111 Small molecule or natural product Click here for species-specific activity table Rn Agonist 5.8 pEC50 3
pEC50 5.8 (EC50 1.7x10-6 M) [3]
(S)-3,4-DCPG Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 5.4 pEC50 27
pEC50 5.4 (EC50 3.98x10-6 M) [27]
LSP4-2022 Small molecule or natural product Click here for species-specific activity table Hs Agonist 5.4 pEC50 11
pEC50 5.4 (EC50 4.4x10-6 M) [11]
(R,S)-4-PPG Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.3 pEC50 9,27
pEC50 5.3 [9,27]
L-CCG-I Small molecule or natural product Click here for species-specific activity table Rn Full agonist 5.2 pEC50 4
pEC50 5.2 [4]
L-glutamic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 5.2 pEC50 15
pEC50 5.2 [15]
L-glutamic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 4.8 pEC50 22
pEC50 4.8 [22]
(1S,3R)-ACPD Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 4.7 pEC50 15
pEC50 4.7 [15]
1-benzyl-APDC Small molecule or natural product Rn Full agonist 4.7 pEC50 28
pEC50 4.7 [28]
L-glutamic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Rn Full agonist 4.4 pEC50 4
pEC50 4.4 [4]
(1S,3R)-ACPD Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Full agonist 4.2 pEC50 28
pEC50 4.2 [28]
homo-AMPA Small molecule or natural product Hs Agonist 4.1 pEC50 5
pEC50 4.1 (EC50 8.2x10-5 M) [5]
LY379268 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 6.4 pIC50 18
pIC50 6.4 [18]
eglumegad Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 5.5 pIC50 18
pIC50 5.5 [18]
ACPT-I Small molecule or natural product Click here for species-specific activity table Rn Full agonist 4.7 pIC50
pIC50 4.7
View species-specific agonist tables
Agonist Comments
1-benzyl-APDC is the only selective agonist for mGlu6 reported.
L-AP4, L-SOP, RS-4-PPG are selective for group III mGlu receptors.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
DCG-IV Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Antagonist 5.6 pEC50 4
pEC50 5.6 [4]
[3H]LY341495 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Antagonist 4.5 pEC50 32
pEC50 4.5 [32]
α-methylserine-O-phosphate Small molecule or natural product Click here for species-specific activity table Rn Antagonist 4.1 pEC50 21
pEC50 4.1 [21]
MAP4 Small molecule or natural product Click here for species-specific activity table Rn Antagonist 3.5 pIC50 21
pIC50 3.5 [21]
MPPG Small molecule or natural product Click here for species-specific activity table Hs Antagonist 3.3 pIC50 16
pIC50 3.3 [16]
View species-specific antagonist tables
Antagonist Comments
There is no specific mGlu6 antagonist.
CPPG, α-MSOP, MAP4 are group III selective antagonists.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PHCCC Small molecule or natural product Click here for species-specific activity table Rn Positive 4.8 pEC50 2
pEC50 4.8 (EC50 1.5x10-5 M) [2]
Allosteric Modulator Comments
PHCCC is a standard mGlu4 positive allosteric modulator; at high concentrations, the compound exhibits agonist activity in certain systems at mGlu6.
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Other - See Comments
Comments:  Glutamate released by photoreceptor cells in the dark stimulates mGlu6 on bipolar cell dendrites, which activates Go, and results in the closure of non-specific, and unidentified, cation channels. Light reduces glutamate stimulation, leading to the opening of channels and the depolarization of On-bipolar cells.
References:  6,31
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Comments:  In transfected cells
References:  13,19
Tissue Distribution Click here for help
Retina: outer part of the inner nuclear layer.
Species:  Rat
Technique:  Northern Blotting and in situ hybridisation.
References:  1
Retina: rod bipolar cells.
Species:  Rat
Technique:  in situ hybridisation.
References:  12
Suprachiasmatic nucleus of hypothalamus.
Species:  Rat
Technique:  RT-PCR.
References:  10
Bone marrow stromal cells.
Species:  Rat
Technique:  Western blotting and RT-PCR.
References:  8
Retina: dendrites of On-bipolar cells.
Species:  Rat
Technique:  Immunohistochemistry.
References:  17
Retina: bipolar cells.
Species:  Rat
Technique:  immunocytochemistry.
References:  20
Retina: On-bipolar cells.
Species:  Rat
Technique:  in situ hybridisation.
References:  19
Expression Datasets Click here for help

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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 Click here for help
Measurement of cAMP levels in CHO cells transfected with the human mGlu receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP accumulation.
References:  15
Measurement of cAMP levels in CHO cells transfected with the rat mGlu6 receptor.
Species:  Rat
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP accumulation.
References:  19
Measurement of transducin and Go activity in lipid vesicles prepared from COS-7 cells transfected with the human mGlu6 receptor.
Species:  Human
Tissue:  Lipid vesicles prepared from COS-7 cells.
Response measured:  Activation of transducin and Go.
References:  31
Measurement of IP levels in HEK 293 cells transfected with the rat mGlu6 receptor and G15.
Species:  Rat
Tissue:  HEK 293
Response measured:  IP formation.
References:  4
Physiological Functions Click here for help
Transduces the light-on signal in retinal On bipolar cells.
Species:  Rat
Tissue:  Retina.
References:  24
Transduces the light-on signal in retinal On bipolar cells.
Species:  Mouse
Tissue:  Retina.
References:  24
Physiological Consequences of Altering Gene Expression Click here for help
mGlu6 knockout mice exhibit deficits in On responses and electroretinogram.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  17
mGlu6 knockout mice exhibit impairment of pupillary responses and optokinetic nystagmus.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  14
mGlu6 knockout mice exhibit abnormalities in wheel-running activity suppression after light-onset.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  26
mGlu6 receptor knockout mice exhibit no abnormality of retinal structure.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  25
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Grm6tm1Nak Grm6tm1Nak/Grm6tm1Nak
involves: 129S/SvEv * C57BL/6 * DBA
MGI:1351343  MP:0005551 abnormal eye electrophysiology PMID: 7889569 
Grm6nob4 Grm6nob4/Grm6nob4
C57BL/6J-Grm6
MGI:1351343  MP:0005551 abnormal eye electrophysiology
Grm6tm1Nak Grm6tm1Nak/Grm6tm1Nak
involves: 129S/SvEv * C57BL/6 * DBA
MGI:1351343  MP:0003635 abnormal synaptic transmission PMID: 7889569 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Night blindness, congenital stationary, type 1B; CSNB1B
Synonyms: Congenital stationary night blindness [Orphanet: ORPHA215] [Disease Ontology: DOID:0050534]
Disease Ontology: DOID:0050534
OMIM: 257270
Orphanet: ORPHA215
Comments: 
References:  7,33
Biologically Significant Variants Click here for help
Type:  Splice variants
Species:  Human
Description:  Splice variants mGlu6(b), mGlu6(c) have been described in humans. In both cases, a stop codon is inserted before the 7TM domain, such that these variants, if produced, may correspond to soluble extracellular proteins not able to activate G-proteins.
References:  29
Type:  Splice variants
Species:  Rat
Description:  Splice variants mGlu6(b), mGlu6(c) have been described in rat. In both cases, a stop codon is inserted before the 7TM domain, such that these variants, if produced, may correspond to soluble extracellular proteins not able to activate G-proteins.
References:  30
General Comments
Schoepp et al., (1999) [23] and Pin & Acher (2002) [21] review and compare the pharmacology of mGlu receptors.

References

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1. Akazawa C, Ohishi H, Nakajima Y, Okamoto N, Shigemoto R, Nakanishi S, Mizuno N. (1994) Expression of mRNAs of L-AP4-sensitive metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7) in the rat retina. Neurosci. Lett., 171 (1-2): 52-4. [PMID:8084499]

2. Beqollari D, Kammermeier PJ. (2008) The mGlu(4) receptor allosteric modulator N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide acts as a direct agonist at mGlu(6) receptors. Eur. J. Pharmacol., 589 (1-3): 49-52. [PMID:18593581]

3. Beurrier C, Lopez S, Révy D, Selvam C, Goudet C, Lhérondel M, Gubellini P, Kerkerian-LeGoff L, Acher F, Pin JP et al.. (2009) Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism. FASEB J., 23 (10): 3619-28. [PMID:19525404]

4. Brabet I, Parmentier ML, De Colle C, Bockaert J, Acher F, Pin JP. (1998) Comparative effect of L-CCG-I, DCG-IV and gamma-carboxy-L-glutamate on all cloned metabotropic glutamate receptor subtypes. Neuropharmacology, 37 (8): 1043-51. [PMID:9833633]

5. Bräuner-Osborne H, Sløk FA, Skjaerbaek N, Ebert B, Sekiyama N, Nakanishi S, Krogsgaard-Larsen P. (1996) A new highly selective metabotropic excitatory amino acid agonist: 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid. J. Med. Chem., 39 (16): 3188-94. [PMID:8759641]

6. Dhingra A, Lyubarsky A, Jiang M, Pugh Jr EN, Birnbaumer L, Sterling P, Vardi N. (2000) The light response of ON bipolar neurons requires G[alpha]o. J. Neurosci., 20 (24): 9053-8. [PMID:11124982]

7. Dryja TP, McGee TL, Berson EL, Fishman GA, Sandberg MA, Alexander KR, Derlacki DJ, Rajagopalan AS. (2005) Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6. Proc. Natl. Acad. Sci. U.S.A., 102 (13): 4884-9. [PMID:15781871]

8. Foreman MA, Gu Y, Howl JD, Jones S, Publicover SJ. (2005) Group III metabotropic glutamate receptor activation inhibits Ca2+ influx and nitric oxide synthase activity in bone marrow stromal cells. J. Cell. Physiol., 204 (2): 704-13. [PMID:15799084]

9. Gasparini F, Bruno V, Battaglia G, Lukic S, Leonhardt T, Inderbitzin W, Laurie D, Sommer B, Varney MA, Hess SD, Johnson EC, Kuhn R, Urwyler S, Sauer D, Portet C, Schmutz M, Nicoletti F, Flor PJ. (1999) (R,S)-4-phosphonophenylglycine, a potent and selective group III metabotropic glutamate receptor agonist is anticonvulsive and neuroprotectivein vivo. J. Pharmacol. Exp. Ther., 289: 1678-1687. [PMID:10336568]

10. Ghosh PK, Baskaran N, van den Pol AN. (1997) Developmentally regulated gene expression of all eight metabotropic glutamate receptors in hypothalamic suprachiasmatic and arcuate nuclei--a PCR analysis. Brain Res. Dev. Brain Res., 102 (1): 1-12. [PMID:9298229]

11. Goudet C, Vilar B, Courtiol T, Deltheil T, Bessiron T, Brabet I, Oueslati N, Rigault D, Bertrand HO, McLean H et al.. (2012) A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential. FASEB J., 26 (4): 1682-93. [PMID:22223752]

12. Hartveit E, Brandstätter JH, Enz R, Wässle H. (1995) Expression of the mRNA of seven metabotropic glutamate receptors (mGluR1 to 7) in the rat retina. An in situ hybridization study on tissue sections and isolated cells. Eur. J. Neurosci., 7 (7): 1472-83. [PMID:7551173]

13. Hashimoto T, Inazawa J, Okamoto N, Tagawa Y, Bessho Y, Honda Y, Nakanishi S. (1997) The whole nucleotide sequence and chromosomal localization of the gene for human metabotropic glutamate receptor subtype 6. Eur. J. Neurosci., 9 (6): 1226-35. [PMID:9215706]

14. Iwakabe H, Katsuura G, Ishibashi C, Nakanishi S. (1997) Impairment of pupillary responses and optokinetic nystagmus in the mGluR6-deficient mouse. Neuropharmacology, 36 (2): 135-43. [PMID:9144650]

15. Laurie DJ, Schoeffter P, Wiederhold KH, Sommer B. (1997) Cloning, distribution and functional expression of the human mGlu6 metabotropic glutamate receptor. Neuropharmacology, 36 (2): 145-52. [PMID:9144651]

16. Ma D, Tian H, Sun H, Kozikowski AP, Pshenichkin S, Wroblewski JT. (1997) Synthesis and biological acitivity of cyclic analogues of MPPG and MCPG as metabotropic glutamate receptor antagonists. Bioorg. Med. Chem. Lett., 7: 1195-1198.

17. Masu M, Iwakabe H, Tagawa Y, Miyoshi T, Yamashita M, Fukuda Y, Sasaki H, Hiroi K, Nakamura Y, Shigemoto R et al.. (1995) Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene. Cell, 80 (5): 757-65. [PMID:7889569]

18. Monn JA, Valli MJ, Massey SM, Hansen MM, Kress TJ, Wepsiec JP, Harkness AR, Grutsch Jr JL, Wright RA, Johnson BG et al.. (1999) 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. J. Med. Chem., 42 (6): 1027-40. [PMID:10090786]

19. Nakajima Y, Iwakabe H, Akazawa C, Nawa H, Shigemoto R, Mizuno N, Nakanishi S. (1993) Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-2-amino-4-phosphonobutyrate. J. Biol. Chem., 268 (16): 11868-73. [PMID:8389366]

20. Nomura A, Shigemoto R, Nakamura Y, Okamoto N, Mizuno N, Nakanishi S. (1994) Developmentally regulated postsynaptic localization of a metabotropic glutamate receptor in rat rod bipolar cells. Cell, 77 (3): 361-9. [PMID:8181056]

21. Pin JP, Acher F. (2002) The metabotropic glutamate receptors: structure, activation mechanism and pharmacology. Curr Drug Targets CNS Neurol Disord, 1 (3): 297-317. [PMID:12769621]

22. Pin JP, De Colle C, Bessis AS, Acher F. (1999) New perspectives for the development of selective metabotropic glutamate receptor ligands. Eur. J. Pharmacol., 375 (1-3): 277-94. [PMID:10443583]

23. Schoepp DD, Jane DE, Monn JA. (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology, 38 (10): 1431-76. [PMID:10530808]

24. Slaughter MM, Miller RF. (1981) 2-amino-4-phosphonobutyric acid: a new pharmacological tool for retina research. Science, 211 (4478): 182-5. [PMID:6255566]

25. Tagawa Y, Sawai H, Ueda Y, Tauchi M, Nakanishi S. (1999) Immunohistological studies of metabotropic glutamate receptor subtype 6-deficient mice show no abnormality of retinal cell organization and ganglion cell maturation. J. Neurosci., 19 (7): 2568-79. [PMID:10087070]

26. Takao M, Morigiwa K, Sasaki H, Miyoshi T, Shima T, Nakanishi S, Nagai K, Fukuda Y. (2000) Impaired behavioral suppression by light in metabotropic glutamate receptor subtype 6-deficient mice. Neuroscience, 97 (4): 779-87. [PMID:10842024]

27. Thomas NK, Wright RA, Howson PA, Kingston AE, Schoepp DD, Jane DE. (2001) (S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord. Neuropharmacology, 40 (3): 311-8. [PMID:11166323]

28. Tuckmantel W, Kozikowski AP, Wang S, Pshenichkin S, Wroblewski JT. (1997) Synthesis, molecular modeling, and biology of the 1-benzyl derivative of APDC-an apparent mGluR6 selective ligand. Bioorg. Med. Chem. Lett., 7: 601-606.

29. Valerio A, Ferraboli S, Paterlini M, Spano P, Barlati S. (2001) Identification of novel alternatively-spliced mRNA isoforms of metabotropic glutamate receptor 6 gene in rat and human retina. Gene., 262: 99-106. [PMID:11179672]

30. Valerio A, Zoppi N, Ferraboli S, Paterlini M, Ferrario M, Barlati S, Spano P. (2001) Alternative splicing of mGlu6 gene generates a truncated glutamate receptor in rat retina. Neuroreport., 12: 2711-2715. [PMID:11522953]

31. Weng K, Lu C, Daggett LP, Kuhn R, Flor PJ, Johnson EC, Robinson PR. (1997) Functional coupling of a human retinal metabotropic glutamate receptor (hmGluR6) to bovine rod transducin and rat Go in an in vitro reconstitution system. J. Biol. Chem., 272 (52): 33100-4. [PMID:9407094]

32. Wright RA, Arnold MB, Wheeler WJ, Ornstein PL, Schoepp DD. (2000) Binding of [3H](2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycyclopropyl) glycine ([3H]LY341495) to cell membranes expressing recombinant human group III metabotropic glutamate receptor subtypes. Naunyn Schmiedebergs Arch. Pharmacol., 362 (6): 546-54. [PMID:11138847]

33. Zeitz C, van Genderen M, Neidhardt J, Luhmann UF, Hoeben F, Forster U, Wycisk K, Mátyás G, Hoyng CB, Riemslag F et al.. (2005) Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram. Invest. Ophthalmol. Vis. Sci., 46 (11): 4328-35. [PMID:16249515]

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