Nomenclature: mGlu6 receptor

Family: Metabotropic glutamate receptors

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing. 

Contents

Gene and Protein Information
class C G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 877 5q35 GRM6 glutamate receptor, metabotropic 6 13,15
Mouse 7 871 11 B1.3 Grm6 glutamate receptor, metabotropic 6
Rat 7 871 10 Grm6 glutamate receptor, metabotropic 6 19
Previous and Unofficial Names
GRM6
Gprc1f
mGluR6
mGlu6
glutamate receptor, metabotropic 6
metabotropic glutamate receptor 6
nob2
nerg1
nob3
BC021919
Gm3
nob4
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligands
L-glutamic acid
Comments: Other endogenous ligands include L-aspartic acid, L-SOP, NAAG and L-cysteine sulphinic acid
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
L-AP4 Hs Full agonist 6.7 – 7.3 pEC50 15,26
pEC50 6.7 – 7.3 [15,26]
L-SOP Hs Full agonist 6.4 pEC50 15
pEC50 6.4 [15]
L-CCG-I Hs Full agonist 6.2 pEC50 15
pEC50 6.2 [15]
LSP1-2111 Rn Agonist 5.77 pEC50 3
pEC50 5.77 (EC50 1.7x10-6 M) [3]
(S)-3,4-DCPG Hs Full agonist 5.4 pEC50 26
pEC50 5.4 [26]
LSP4-2022 Hs Agonist 5.36 pEC50 11
pEC50 5.36 (EC50 4.4x10-6 M) [11]
(R,S)-4-PPG Hs Full agonist 5.3 pEC50 9,26
pEC50 5.3 [9,26]
L-glutamic acid Hs Full agonist 5.2 pEC50 15
pEC50 5.2 [15]
L-CCG-I Rn Full agonist 5.2 pEC50 4
pEC50 5.2 [4]
1-benzyl-APDC Rn Full agonist 4.7 pEC50 27
pEC50 4.7 [27]
(1S,3R)-ACPD Hs Full agonist 4.7 pEC50 15
pEC50 4.7 [15]
L-glutamic acid Rn Full agonist 4.4 pEC50 4
pEC50 4.4 [4]
(1S,3R)-ACPD Rn Full agonist 4.2 pEC50 27
pEC50 4.2 [27]
homo-AMPA Hs Agonist 4.1 pEC50 5
pEC50 4.1 (EC50 8.2x10-5 M) [5]
LY379268 Hs Full agonist 6.4 pIC50 18
pIC50 6.4 [18]
eglumegad Hs Full agonist 5.5 pIC50 18
pIC50 5.5 [18]
ACPT-I 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 Affinity Units Reference
DCG-IV Rn Antagonist 5.6 pEC50 4
pEC50 5.6 [4]
[3H]LY341495 Hs Antagonist 4.5 pEC50 31
pEC50 4.5 [31]
MSOP Rn Antagonist 4.1 pEC50 21
pEC50 4.1 [21]
MAP4 Rn Antagonist 3.5 pIC50 21
pIC50 3.5 [21]
MPPG 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 Affinity Units Reference
PHCCC 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
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:  6,30
Secondary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Comments:  In transfected cells
References:  13,19
Tissue Distribution
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
Retina: outer part of the inner nuclear layer.
Species:  Rat
Technique:  Northern Blotting and in situ hybridisation.
References:  1
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
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:  30
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
Transduces the light-on signal in retinal On bipolar cells.
Species:  Rat
Tissue:  Retina.
References:  23
Transduces the light-on signal in retinal On bipolar cells.
Species:  Mouse
Tissue:  Retina.
References:  23
Physiological Consequences of Altering Gene Expression
mGlu6 knockout mice exhibit abnormalities in wheel-running activity suppression after light-onset.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  25
mGlu6 receptor knockout mice exhibit no abnormality of retinal structure.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  24
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
Phenotypes, Alleles and Disease Models 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
Disease:  Congenital stationary night blindness
OMIM:  257270
Orphanet:  215
Comments: 
References:  7,32
Mutations not determined
Biologically Significant Variants
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:  28
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:  29
General Comments
Schoepp et al., (1999) [22] and Pin & Acher (2002) [21] review and compare the pharmacology of mGlu receptors.

REFERENCES

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: 52-54. [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: 1043-1051. [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 EN Jr, Birnbaumer L, Sterling P, Vardi N. (2000) The light response of ON bipolar neurons requires G[alpha]o. J Neurosci.20: 9053-9058. [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: 4884-4889. [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 Physiol204: 704-713. [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: 1-12. [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 Neurosci7: 1472-1483. [PMID:7551173]

13. Hashimoto T, Inazawa J, Okamoto N, Tagawa Y, Bessho Y, Honda Y, Nakanishi S. (1997) The whole nucleotide sequence and chromosomallocalization of the gene for human metabotropic glutamate receptor subtype 6. Eur. J. Neurosci.9: 1226-1235. [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: 135-143. [PMID:9144650]

15. Laurie DJ, Schoeffter P, Wiederhold KH, Sommer B. (1997) Cloning, distribution and functional expression of the human mGlu6 metabotropic glutamate receptor. Neuropharmacology36: 145-152. [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: 757-765. [PMID:7889569]

18. 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. (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: 1027- 1040. [PMID:10090786]

19. Nakajima Y, Iwakabe H, Akazawa C, Nawa H, Shigemoto R, Mizuno R, 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: 11868-11873. [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. Cell77: 361-369. [PMID:8181056]

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

22. Schoepp DD, Jane DE, Monn JA. (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology38: 1431-1476. [PMID:10530808]

23. Slaughter MM, Miller RF. (1981) 2-amino-4-phosphonobutyric acid: a new pharmacological tool for retina research. Science.211: 182-185. [PMID:6255566]

24. 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: 2568-2579. [PMID:10087070]

25. 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: 779-787. [PMID:10842024]

26. 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: 311-318. [PMID:11166323]

27. 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.

28. 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]

29. 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]

30. 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: 33100-33104. [PMID:9407094]

31. 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: 546-554. [PMID:11138847]

32. Zeitz C, van Genderen M, Neidhardt J, Luhmann UF, Hoeben F, Forster U, Wycisk K, Mátyás G, Hoyng CB, Riemslag F, Meire F, Cremers FP, Berger W. (2005) Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram. Invest Ophthalmol Vis Sci46: 4328-4335. [PMID:16249515]

To cite this database page, please use the following:

Francine Acher, P. Jeffrey Conn, Robert Duvoisin, Francesco Ferraguti, Peter J. Flor, David Hampson, Michael P. Johnson, James Monn, Shigetada Nakanishi, Ferdinando Nicoletti, Jean-Philippe Pin, Darryle D. Schoepp, Ryuichi Shigemoto.
Metabotropic glutamate receptors: mGlu6 receptor. Last modified on 12/05/2014. Accessed on 26/07/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=294.

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