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mGlu6 receptor

Family: Metabotropic glutamate receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Biologically Significant Variants
General Comments
References
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 10,12
Mouse 7 871 11 B1.3 Grm6 glutamate receptor, metabotropic 6
Rat 7 871 10 Grm6 glutamate receptor, metabotropic 6 16
Previous and Unofficial Names
mGluR6
GRM6
Gprc1f
mGlu6
glutamate receptor, metabotropic 6
metabotropic glutamate receptor 6
nob2
nerg1
nob3
BC021919
Gm3
nob4
Database Links
ChEMBL Target 11055 (Hs), 11056 (Rn)
Ensembl ENSG00000113262 (Hs), ENSMUSG00000000617 (Mm), ENSRNOG00000000233 (Rn)
Entrez Gene 2916 (Hs), 108072 (Mm), 24419 (Rn)
GeneCards GRM6 (Hs)
GenitoUrinary Development Molecular Anatomy Project Grm6 (Mm)
HomoloGene 20232 (Hs)
Human Protein Reference Database 04975 (Hs)
InterPro O15303 (Hs), Q5NCH9 (Mm), P35349 (Rn)
KEGG Gene hsa:2916 (Hs), mmu:108072 (Mm), rno:24419 (Rn)
OMIM 604096 (Hs)
Orphanet Gene ORPHA122291 (Hs)
PharmGKB Gene PA28995 (Hs)
PhosphoSitePlus O15303 (Hs), Q5NCH9 (Mm), P35349 (Rn)
Protein Ontology (PRO) PRO:000008268 (Hs)
RefSeq Nucleotide NM_000843 (Hs), NM_173372 (Mm), NM_022920 (Rn)
RefSeq Protein NP_000834 (Hs), NP_775548 (Mm), NP_075209 (Rn)
TreeFam ENSG00000113262 (Hs), ENSMUSG00000000617 (Mm), ENSRNOG00000000233 (Rn)
UniGene Hs. 248131 (Hs)
UniProt O15303 (Hs), Q5NCH9 (Mm), P35349 (Rn)
Wikipedia mGlu6 receptor
Metabotropic glutamate receptors
Search for 3D structures on the PDB
Search by keyword: Metabotropic glutamate receptors mGlu6 receptor Search by accession number: P35349, O15303, Q5NCH9
Natural/Endogenous Ligand(s)
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 12,23
L-SOP Hs Full agonist 6.4 pEC50 12
(2S,1S,2S)-L-CCG-I Hs Full agonist 6.2 pEC50 12
(S)-3,4-DCPG Hs Full agonist 5.4 pEC50 23
(R,S)-4-PPG Hs Full agonist 5.3 pEC50 7,23
(2S,1S,2S)-L-CCG-I Rn Full agonist 5.2 pEC50 2
L-glutamic acid Hs Full agonist 5.2 pEC50 12
1-benzyl-APDC Rn Full agonist 4.7 pEC50 24
(1S,3R)-ACPD Hs Full agonist 4.7 pEC50 12
L-glutamic acid Rn Full agonist 4.4 pEC50 2
(1S,3R)-ACPD Rn Full agonist 4.2 pEC50 24
homo-AMPA Hs Agonist 4.1 pEC50 3
LY379268 Hs Full agonist 6.4 pIC50 15
LY354740 Hs Full agonist 5.5 pIC50 15
ACPT-I Rn Full agonist 4.7 pIC50
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 2
[3H]LY341495 Hs Antagonist 4.5 pEC50 28
MSOP Rn Antagonist 4.1 pEC50 18
MAP4 Rn Antagonist 3.5 pIC50 18
MPPG Hs Antagonist 3.3 pIC50 13
View species-specific antagonist tables
Antagonist Comments
There is no specific mGlu6 antagonist.
CPPG, α-MSOP, MAP4 are group III selective antagonists.

Explore drug-target interactions for this set of compounds using iPHACE

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:  4,27
Secondary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Comments:  In transfected cells
References:  10,16
Tissue Distribution
Retina: On-bipolar cells.
Species:  Rat
Technique:  in situ hybridisation.
References:  16
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:  9
Suprachiasmatic nucleus of hypothalamus.
Species:  Rat
Technique:  RT-PCR.
References:  8
Bone marrow stromal cells.
Species:  Rat
Technique:  Western blotting and RT-PCR.
References:  6
Retina: dendrites of On-bipolar cells.
Species:  Rat
Technique:  Immunohistochemistry.
References:  14
Retina: bipolar cells.
Species:  Rat
Technique:  immunocytochemistry.
References:  17
Expression Datasets

Click here to show/hide data

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:  12
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:  16
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:  27
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:  2
Physiological Functions
Transduces the light-on signal in retinal On bipolar cells.
Species:  Rat
Tissue:  Retina.
References:  20
Transduces the light-on signal in retinal On bipolar cells.
Species:  Mouse
Tissue:  Retina.
References:  20
Physiological Consequences of Altering Gene Expression
mGlu6 receptor knockout mice exhibit no abnormality of retinal structure.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  21
mGlu6 knockout mice exhibit impairment of pupillary responses and optokinetic nystagmus.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  11
mGlu6 knockout mice exhibit abnormalities in wheel-running activity suppression after light-onset.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  22
mGlu6 knockout mice exhibit deficits in On responses and electroretinogram.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  14
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

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:  Single nucleotide polymorphisms. Loss of function mutations in the human mGlu6 gene are associated with night blindness and abnormal cone electroretinogram ON responses.
References:  5,29
Mutations not determined
Biologically Significant Variants
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.
Type:  Splice variants.
Species:  Human
References:  25
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.
Type:  Splice variants.
Species:  Rat
References:  26
General Comments
Schoepp et al., (1999) [19] and Pin & Acher (2002) [18] 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. and 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. Brabet, I., Parmentier, M. L., de Colle, C., Bockaert, J., Acher, F. and Pin, J. P. (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]

3. 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]

4. Dhingra, A., Lyubarsky, A., Jiang, M., Pugh EN, J. r., Birnbaumer, L., Sterling, P. and Vardi, N. (2000) The light response of ON bipolar neurons requires G[alpha]o. J Neurosci., 20: 9053-9058. [PMID:11124982]

5. Dryja, T. P., McGee, T. L., Berson, E. L., Fishman, G. A., Sandberg, M. A., Alexander, K. R., Derlacki, D. J. and Rajagopalan, A. S. (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]

6. Foreman, M. A., Gu, Y., Howl, J. D., Jones, S. and Publicover, S. J. (2005) Group III metabotropic glutamate receptor activation inhibits Ca2+ influx and nitric oxide synthase activity in bone marrow stromal cells. J Cell Physiol, 204: 704-713. [PMID:15799084]

7. Gasparini, F., Bruno, V., Battaglia, G., Lukic, S., Leonhardt, T., Inderbitzin, W., Laurie, D., Sommer, B., Varney, M. A., Hess, S. D., Johnson, E. C., Kuhn, R., Urwyler, S., Sauer, D., Portet, C., Schmutz, M., Nicoletti, F. and Flor, P. J. (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]

8. Ghosh, P. K., Baskaran, N. and Van den Pol, A. N. (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]

9. Hartveit, E., Brandstätter, J. H., Enz, R. and 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: 1472-1483. [PMID:7551173]

10. Hashimoto, T., Inazawa, J., Okamoto, N., Tagawa, Y., Bessho, Y., Honda, Y. and 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]

11. Iwakabe, H., Katsuura, G., Ishibashi, C. and Nakanishi, S. (1997) Impairment of pupillary responses and optokinetic nystagmus in the mGluR6-deficient mouse. Neuropharmacology., 36: 135-143. [PMID:9144650]

12. Laurie, D. J., Schoeffter, P., Wiederhold, K. H. and Sommer, B. (1997) Cloning, distribution and functional expression of the human mGlu6 metabotropic glutamate receptor. Neuropharmacology, 36: 145-152. [PMID:9144651]

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

14. Masu, M., Iwakabe, H., Tagawa, Y., Miyoshi, T., Yamashita, M., Fukuda, Y., Sasaki, H., Hiroi, K., Nakamura, Y., Shigemoto, R. and et, a. l. (1995) Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene. Cell., 80: 757-765. [PMID:7889569]

15. Monn, J. A., Valli, M. J., Massey, S. M., Hansen, M. M., Kress, T. J., Wepsiec, J. P., Harkness, A. R., Grutsch, J. L., Wright, R. A., Johnson, B. G., Andis, S. L., Kingston, A., Tomlinson, R., Lewis, R., Griffey, K. R., Tizzano, J. P. and Schoepp, D. D. (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]

16. Nakajima, Y., Iwakabe, H., Akazawa, C., Nawa, H., Shigemoto, R., Mizuno, R. and 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]

17. Nomura, A., Shigemoto, R., Nakamura, Y., Okamoto, N., Mizuno, N. and Nakanishi, S. (1994) Developmentally regulated postsynaptic localization of a metabotropic glutamate receptor in rat rod bipolar cells. Cell, 77: 361-369. [PMID:8181056]

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

19. Schoepp, D. D., Jane, D. E. and Monn, J. A. (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology, 38: 1431-1476. [PMID:10530808]

20. Slaughter, M. M. and Miller, R. F. (1981) 2-amino-4-phosphonobutyric acid: a new pharmacological tool for retina research. Science., 211: 182-185. [PMID:6255566]

21. Tagawa, Y., Sawai, H., Ueda, Y., Tauchi, M. and 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]

22. Takao, M., Morigiwa, K., Sasaki, H., Miyoshi, T., Shima, T., Nakanishi, S., Nagai, K. and Fukuda, Y. (2000) Impaired behavioral suppression by light in metabotropic glutamate receptor subtype 6-deficient mice. Neuroscience., 97: 779-787. [PMID:10842024]

23. Thomas, N. K., Wright, R. A., Howson, P. A., Kingston, A. E., Schoepp, D. D. and Jane, D. E. (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]

24. Tuckmantel, W., Kozikowski, A. P., Wang, S., Pshenichkin, S. and Wroblewski, J. T. (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.

25. Valerio, A., Ferraboli, S., Paterlini, M., Spano, P. and 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]

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

27. Weng, K., Lu, C., Daggett, L. P., Kuhn, R., Flor, P. J., Johnson, E. C. and Robinson, P. R. (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]

28. Wright, R. A., Arnold, M. B., Wheeler, W. J., Ornstein, P. L. and Schoepp, D. D. (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]

29. Zeitz, C., van Genderen, M., Neidhardt, J., Luhmann, U. F., Hoeben, F., Forster, U., Wycisk, K., Mátyás, G., Hoyng, C. B., Riemslag, F., Meire, F., Cremers, F. P. and Berger, W. (2005) Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram. Invest Ophthalmol Vis Sci, 46: 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 31/01/2013. Accessed on 25/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=294.


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