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Gene and Protein Information | ||||||
class C G protein-coupled receptor | ||||||
Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 7 | 1212 | 11q14.2-q14.3 | GRM5 | glutamate metabotropic receptor 5 | 60-61 |
Mouse | 7 | 1203 | 7 D3 | Grm5 | glutamate receptor, metabotropic 5 | |
Rat | 7 | 1203 | 1q32 | Grm5 | glutamate metabotropic receptor 5 | 1,41 |
Previous and Unofficial Names |
mGluR5 | GPRC1E | glutamate receptor |
Database Links | |
Specialist databases | |
GPCRdb | grm5_human (Hs), grm5_mouse (Mm), grm5_rat (Rn) |
Other databases | |
Alphafold | P41594 (Hs), Q3UVX5 (Mm), P31424 (Rn) |
ChEMBL Target | CHEMBL3227 (Hs), CHEMBL1641352 (Mm), CHEMBL2564 (Rn) |
DrugBank Target | P41594 (Hs) |
Ensembl Gene | ENSG00000168959 (Hs), ENSMUSG00000049583 (Mm), ENSRNOG00000016429 (Rn) |
Entrez Gene | 2915 (Hs), 108071 (Mm), 24418 (Rn) |
Human Protein Atlas | ENSG00000168959 (Hs) |
KEGG Gene | hsa:2915 (Hs), mmu:108071 (Mm), rno:24418 (Rn) |
OMIM | 604102 (Hs) |
Pharos | P41594 (Hs) |
RefSeq Nucleotide | NM_000842 (Hs), NM_001143831 (Hs), NM_001081414 (Mm), NM_017012 (Rn) |
RefSeq Protein | NP_001137303 (Hs), NP_000833 (Hs), NP_001074883 (Mm), NP_058708 (Rn) |
UniProtKB | P41594 (Hs), Q3UVX5 (Mm), P31424 (Rn) |
Wikipedia | GRM5 (Hs) |
Selected 3D Structures | |||||||||||||
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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
Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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View species-specific agonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Indicated affinities were determined by displacement studies of [3H]quisqualate bound on HEK cell membranes expressing a recombinant rat mGlu5. This is the only study describing affinity values for these compounds. More information on agonist potencies determined from functional studies can be obtained from [85]. So far no differences have been reported for the agonist affinities between the rat and the human receptor. |
Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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View species-specific antagonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Indicated affinities were determined by displacement studies of [3H]quisqualate bound on HEK cell membranes expressing a recombinant rat mGlu5 (except for LY341495 value determined from functional studies). This is the only study describing affinity values for these compounds. More information on agonist potencies determined from functional studies can be obtained from [85]. So far no differences have been reported for the antagonist affinities between the rat and the human receptor. Surprisingly, although LY367385 and AIDA displace Quisqualate binding, no antagonistic activity of these compounds have been observed in functional studies (see [85]). (S)-4C3HPG has been reported to have slight partial agonist activity at this receptor [41]. |
Allosteric Modulators | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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View species-specific allosteric modulator tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allosteric Modulator Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
M-5MPEP is a partal antagonist at the rat receptor [78]. Allosteric regulators, either negative (non-competitive antagonists), positive (allosteric potentiators), or neutral, are usually highly selective for mGlu5, being inactive on the highly homologous mGlu1 receptor. These modulators bind in the 7TM region of the receptor [54,68], whereas the orthosteric site is located in the large extracellular domain of this receptor. A second important point is that many negative modulators possess inverse agonist activity. However, allosteric "partial antagonists" have now been discovered [78]. The concept of partial antagonist activity is novel and can only be achieved with compounds acting at an allosteric site. Although a clear interaction between DFB, CDPPB and the MPEP binding site has been described, the relationship between binding to this site and allosteric potentiation is not yet clear. CPPHA clearly binds at a site different from MPEP [67]. DCB and 5MPEP have been shown to inhibit the effect of both positive and negative allosteric modulators, and represents as such a novel type of modulator called a neutral allosteric site ligand [66,78]. M-5MPEP and Br5-MPEPy fully displace binding of [3H]methoxyPEPy but do not fully block glutamate responses [78]. VU0357121 binds to a site other than the MPEP site [33]. VU0365396 is a non-MPEP site, neutral allosteric ligand [33]. [18F]FPEB has been used in receptor occupancy in humans [96,104]. |
Primary Transduction Mechanisms | |
Transducer | Effector/Response |
Gq/G11 family | Phospholipase C stimulation |
Comments: The main action of mGlu5 is to activate PLC via Gq/11. This can be measured via the inositol phosphate production or increase in intracelular Ca2+ both in cell lines expressing this recombinant receptor or in native tissue such as brain slices or cultured neurons or astrocytes. | |
References: 18,73 |
Secondary Transduction Mechanisms | |
Transducer | Effector/Response |
Gs family Gi/Go family |
Adenylyl cyclase stimulation Potassium channel Calcium channel Phospholipase A2 stimulation Phospholipase D stimulation Other - See Comments |
Comments:
Stimulation of adenylyl cyclase has been reported in transfected cell lines, and in native tissue although it is not yet known whether this effect is due to mGlu5 or mGlu1 or both [18]. Coupling of group-I mGlu receptors to PTX-sensitive G-proteins Gi and Go has also been observed in many cells including neurons. Such a coupling is at the origin of MAPK activation. Activation of PLA2 is potentiated by co-activation of the NMDA receptor [24]. PLD activation has been reported both in brain slices [46] and in cultured astrocytes [86]. However, some studies reported this response may also be generated by an mglu receptor with specific pharmacological properties [7,18]. Activation of big potassium currents likely results from the increase in intracellular Ca2+. However, inhibition of various type of potassium currents lead to an increase in cell excitability [4]. Both inhibition and potentiation of voltage sensitive Ca2+ channels (N and L types) have been reported [4,18,73]. |
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References: 4,18,73 |
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Expression Datasets | |
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Physiological Functions | ||||||||
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Physiological Consequences of Altering Gene Expression | ||||||||||
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Phenotypes, Alleles and Disease Models | Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Biologically Significant Variants | ||||||||
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12. Burdi DF, Hunt R, Fan L, Hu T, Wang J, Guo Z, Huang Z, Wu C, Hardy L, Detheux M et al.. (2010) Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5. J Med Chem, 53 (19): 7107-18. [PMID:20809633]
13. Büttelmann B, Peters JU, Ceccarelli S, Kolczewski S, Vieira E, Prinssen EP, Spooren W, Schuler F, Huwyler J, Porter RH et al.. (2006) Arylmethoxypyridines as novel, potent and orally active mGlu5 receptor antagonists. Bioorg Med Chem Lett, 16 (7): 1892-7. [PMID:16439120]
14. Ceccarelli SM, Jaeschke G, Buettelmann B, Huwyler J, Kolczewski S, Peters JU, Prinssen E, Porter R, Spooren W, Vieira E. (2007) Rational design, synthesis, and structure-activity relationship of benzoxazolones: new potent mglu5 receptor antagonists based on the fenobam structure. Bioorg Med Chem Lett, 17 (5): 1302-6. [PMID:17189691]
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17. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F. (2001) Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci, 4 (9): 873-4. [PMID:11528416]
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