Metabotropic glutamate receptor 4

GRM4
Identifiers
Aliases	GRM4, GPRC1D, MGLUR4, mGlu4, glutamate metabotropic receptor 4
External IDs	OMIM: 604100; MGI: 1351341; HomoloGene: 20230; GeneCards: GRM4; OMA:GRM4 - orthologs
Gene location (Human)
Chr.	Chromosome 6 (human)
End	34,155,622 bp
Gene location (Mouse)
Chr.	Chromosome 17 (mouse)
End	27,740,377 bp
RNA expression pattern
	Top expressed in
	paraflocculus of cerebellum; ; right hemisphere of cerebellum; ; cerebellar vermis; ; nucleus accumbens; ; putamen; ; caudate nucleus; ; Brodmann area 10; ; middle frontal gyrus; ; islet of Langerhans; ; quadriceps femoris muscle;
	Top expressed in
	cerebellar cortex; ; cerebellar vermis; ; lobe of cerebellum; ; zygote; ; secondary oocyte; ; medial dorsal nucleus; ; primary oocyte; ; medial geniculate nucleus; ; olfactory tubercle; ; nucleus of stria terminalis;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	glutamate receptor activity; G protein-coupled receptor activity; signal transducer activity;
Cellular component	integral component of membrane; plasma membrane; integral component of plasma membrane; intracellular anatomical structure; presynaptic membrane; cytoplasmic vesicle; membrane;
Biological process	regulation of neuron apoptotic process; adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway; neurotransmitter secretion; positive regulation of MAPK cascade; signal transduction; chemical synaptic transmission; regulation of synaptic transmission, glutamatergic; G protein-coupled receptor signaling pathway; G protein-coupled glutamate receptor signaling pathway;
	Sources:Amigo / QuickGO
Orthologs
	2914
	268934
	ENSG00000124493
	ENSMUSG00000063239
	Q14833
	Q68EF4
NM_000841; NM_001256809; NM_001256810; NM_001256811; NM_001256812;
	NM_001256813; NM_001256814; NM_001282847
	NM_001013385; NM_001291045; NM_001360192; NM_001379317
NP_000832; NP_001243738; NP_001243740; NP_001243741; NP_001243742;
	NP_001269776
	NP_001013403; NP_001277974; NP_001347121
	Wikidata
View/Edit Human	View/Edit Mouse

Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.^[5]^[6]^[7]

Together with GRM6, GRM7 and GRM8 it belongs to group III of the metabotropic glutamate receptor family. Group III receptors are linked to the inhibition of the cyclic AMP cascade.^[7] Activation of GRM4 has potential therapeutic benefits in the treatment of parkinson's disease. Splice variant "taste-GRM4" is involved in the perception of umami taste.^[8]

Ligands

Orthosteric

Cinnabarinic acid, a tryptophan metabolite^[9]
LSP1-2111: agonist^[10]
LSP4-2022: agonist^[11]
LSP2-9166: mixed agonist at mGluR₄ and mGluR₇

Positive allosteric modulators (PAMs)

Foliglurax (PXT-002331, DT-1687)
Tricyclic thiazolopyrazole derivative 22a: EC₅₀ = 9 nM, E_max = 120%^[12]
ML-128: EC₅₀ = 240 nM, E_max = 182%^[13]^[14]
VU0652957 (AP-472) (Valiglurax)^[15]
VU-0418506^[16]^[17]
VU-001171: EC₅₀ = 650 nM, E_max = 141%, 36-fold shift^[18]
VU-0155041: subtype-selective PAM, intrinsic allosteric agonist activity, robust in-vivo activity^[19]
PHCCC: PAM of mGluR4, negative allosteric modulator of mGluR1,^[20] direct agonist at mGluR6^[21]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000124493 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000063239 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Makoff A, Lelchuk R, Oxer M, Harrington K, Emson P (April 1996). "Molecular characterization and localization of human metabotropic glutamate receptor type 4". Brain Research. Molecular Brain Research. 37 (1–2): 239–248. doi:10.1016/0169-328X(95)00321-I. PMID 8738157.
^ Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR, et al. (January 1998). "Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells". Brain Research. Molecular Brain Research. 53 (1–2): 88–97. doi:10.1016/S0169-328X(97)00277-5. PMID 9473604.
^ ^a ^b "Entrez Gene: GRM4 glutamate receptor, metabotropic 4".
^ Chaudhari N, Landin AM, Roper SD (February 2000). "A metabotropic glutamate receptor variant functions as a taste receptor". Nature Neuroscience. 3 (2): 113–119. doi:10.1038/72053. PMID 10649565. S2CID 16650588.
^ Fazio F, Lionetto L, Molinaro G, Bertrand HO, Acher F, Ngomba RT, et al. (May 2012). "Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors". Molecular Pharmacology. 81 (5): 643–656. doi:10.1124/mol.111.074765. PMID 22311707. S2CID 6735807.
^ Wierońska JM, Stachowicz K, Pałucha-Poniewiera A, Acher F, Brański P, Pilc A (December 2010). "Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems". Neuropharmacology. 59 (7–8): 627–634. doi:10.1016/j.neuropharm.2010.08.008. PMID 20713068. S2CID 5171741.
^ Goudet C, Vilar B, Courtiol T, Deltheil T, Bessiron T, Brabet I, et al. (April 2012). "A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential". FASEB Journal. 26 (4): 1682–1693. doi:10.1096/fj.11-195941. PMID 22223752. S2CID 22662090.
^ Hong SP, Liu KG, Ma G, Sabio M, Uberti MA, Bacolod MD, et al. (July 2011). "Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators". Journal of Medicinal Chemistry. 54 (14): 5070–5081. doi:10.1021/jm200290z. PMID 21688779.
^ Hopkins CR, Niswender CM, Lewis LM, Weaver CD, Lindsley CW (2010). "Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator". Probe Reports from the NIH Molecular Libraries Program [Internet]. PMID 21433377.
^ Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon UN, Zamorano R, et al. (July 2009). "Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs)". Journal of Medicinal Chemistry. 52 (14): 4115–4118. doi:10.1021/jm9005065. PMC 2765192. PMID 19469556.
^ Panarese JD, Engers DW, Wu YJ, Bronson JJ, Macor JE, Chun A, et al. (March 2019). "Discovery of VU2957 (Valiglurax): An mGlu₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease". ACS Medicinal Chemistry Letters. 10 (3): 255–260. doi:10.1021/acsmedchemlett.8b00426. PMC 6421540. PMID 30891122.
^ Niswender CM, Jones CK, Lin X, Bubser M, Thompson Gray A, Blobaum AL, et al. (September 2016). "Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers". ACS Chemical Neuroscience. 7 (9): 1201–1211. doi:10.1021/acschemneuro.6b00036. PMC 5073817. PMID 27441572.
^ Engers DW, Blobaum AL, Gogliotti RD, Cheung YY, Salovich JM, Garcia-Barrantes PM, et al. (September 2016). "Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4)". ACS Chemical Neuroscience. 7 (9): 1192–1200. doi:10.1021/acschemneuro.6b00035. PMC 5031509. PMID 27075300.
^ Williams R, Niswender CM, Luo Q, Le U, Conn PJ, Lindsley CW (February 2009). "Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead". Bioorganic & Medicinal Chemistry Letters. 19 (3): 962–966. doi:10.1016/j.bmcl.2008.11.104. PMC 3787871. PMID 19097893.
^ Niswender CM, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, et al. (November 2008). "Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4". Molecular Pharmacology. 74 (5): 1345–1358. doi:10.1124/mol.108.049551. PMC 2574552. PMID 18664603.
^ Watkins JC, Jane DE (January 2006). "The glutamate story". British Journal of Pharmacology. 147 (Suppl 1): S100–S108. doi:10.1038/sj.bjp.0706444. PMC 1760733. PMID 16402093.
^ Beqollari D, Kammermeier PJ (July 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". European Journal of Pharmacology. 589 (1–3): 49–52. doi:10.1016/j.ejphar.2008.06.054. PMID 18593581.

Flor PJ, Lukic S, Rüegg D, Leonhardt T, Knöpfel T, Kuhn R (February 1995). "Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 4". Neuropharmacology. 34 (2): 149–155. doi:10.1016/0028-3908(94)00149-M. PMID 7617140. S2CID 31399907.
Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC (January 1996). "Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q". Genomics. 31 (2): 230–233. doi:10.1006/geno.1996.0036. PMID 8824806.
Gomeza J, Mary S, Brabet I, Parmentier ML, Restituito S, Bockaert J, et al. (October 1996). "Coupling of metabotropic glutamate receptors 2 and 4 to G alpha 15, G alpha 16, and chimeric G alpha q/i proteins: characterization of new antagonists". Molecular Pharmacology. 50 (4): 923–930. PMID 8863838.
Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi-Baez L, et al. (July 2000). "p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation". The Journal of Biological Chemistry. 275 (27): 20853–20860. doi:10.1074/jbc.M000660200. PMID 10779504.
Barbon A, Ferraboli S, Barlati S (2000). "Assignment of the human metabotropic glutamate receptor gene GRM4 to chromosome 6 band p21.3 by radiation hybrid mapping". Cytogenetics and Cell Genetics. 88 (3–4): 210. doi:10.1159/000015551. PMID 10828590. S2CID 85055574.
Ohtsuki T, Toru M, Arinami T (June 2001). "Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia". Psychiatric Genetics. 11 (2): 79–83. doi:10.1097/00041444-200106000-00004. PMID 11525421. S2CID 752064.
Erdemir T, Bilican B, Oncel D, Goding CR, Yavuzer U (January 2002). "DNA damage-dependent interaction of the nuclear matrix protein C1D with Translin-associated factor X (TRAX)". Journal of Cell Science. 115 (Pt 1): 207–216. doi:10.1242/jcs.115.1.207. PMID 11801738.
Collard CD, Park KA, Montalto MC, Alapati S, Buras JA, Stahl GL, et al. (April 2002). "Neutrophil-derived glutamate regulates vascular endothelial barrier function". The Journal of Biological Chemistry. 277 (17): 14801–14811. doi:10.1074/jbc.M110557200. PMID 11847215.
Enz R (March 2002). "The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7". FEBS Letters. 514 (2–3): 184–188. Bibcode:2002FEBSL.514..184E. doi:10.1016/S0014-5793(02)02361-X. PMID 11943148. S2CID 44474808.
Gaughan L, Logan IR, Cook S, Neal DE, Robson CN (July 2002). "Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor". The Journal of Biological Chemistry. 277 (29): 25904–25913. doi:10.1074/jbc.M203423200. PMID 11994312.
Iacovelli L, Capobianco L, Iula M, Di Giorgi Gerevini V, Picascia A, Blahos J, et al. (May 2004). "Regulation of mGlu4 metabotropic glutamate receptor signaling by type-2 G-protein coupled receptor kinase (GRK2)". Molecular Pharmacology. 65 (5): 1103–1110. doi:10.1124/mol.65.5.1103. PMID 15102938.
Hermit MB, Greenwood JR, Bräuner-Osborne H (August 2004). "Mutation-induced quisqualic acid and ibotenic acid affinity at the metabotropic glutamate receptor subtype 4: ligand selectivity results from a synergy of several amino acid residues". The Journal of Biological Chemistry. 279 (33): 34811–34817. doi:10.1074/jbc.M404109200. PMID 15184361.
Yoo BC, Jeon E, Hong SH, Shin YK, Chang HJ, Park JG (June 2004). "Metabotropic glutamate receptor 4-mediated 5-Fluorouracil resistance in a human colon cancer cell line". Clinical Cancer Research. 10 (12 Pt 1): 4176–4184. doi:10.1158/1078-0432.CCR-1114-03. PMID 15217955.
Chang HJ, Yoo BC, Lim SB, Jeong SY, Kim WH, Park JG (May 2005). "Metabotropic glutamate receptor 4 expression in colorectal carcinoma and its prognostic significance". Clinical Cancer Research. 11 (9): 3288–3295. doi:10.1158/1078-0432.CCR-04-1912. PMID 15867225.
Mathiesen JM, Ramirez MT (June 2006). "The metabotropic glutamate receptor 4 is internalized and desensitized upon protein kinase C activation". British Journal of Pharmacology. 148 (3): 279–290. doi:10.1038/sj.bjp.0706733. PMC 1751557. PMID 16582932.
Iacovelli L, Arcella A, Battaglia G, Pazzaglia S, Aronica E, Spinsanti P, et al. (August 2006). "Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas". The Journal of Neuroscience. 26 (32): 8388–8397. doi:10.1523/JNEUROSCI.2285-06.2006. PMC 6673797. PMID 16899734.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000124493 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000063239 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid8738157-5] Makoff A, Lelchuk R, Oxer M, Harrington K, Emson P (April 1996). "Molecular characterization and localization of human metabotropic glutamate receptor type 4". Brain Research. Molecular Brain Research. 37 (1–2): 239–248. doi:10.1016/0169-328X(95)00321-I. PMID 8738157.

[pmid9473604-6] Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR, et al. (January 1998). "Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells". Brain Research. Molecular Brain Research. 53 (1–2): 88–97. doi:10.1016/S0169-328X(97)00277-5. PMID 9473604.

[entrez-7] "Entrez Gene: GRM4 glutamate receptor, metabotropic 4".

[pmid10649565-8] Chaudhari N, Landin AM, Roper SD (February 2000). "A metabotropic glutamate receptor variant functions as a taste receptor". Nature Neuroscience. 3 (2): 113–119. doi:10.1038/72053. PMID 10649565. S2CID 16650588.

[9] Fazio F, Lionetto L, Molinaro G, Bertrand HO, Acher F, Ngomba RT, et al. (May 2012). "Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors". Molecular Pharmacology. 81 (5): 643–656. doi:10.1124/mol.111.074765. PMID 22311707. S2CID 6735807.

[10] Wierońska JM, Stachowicz K, Pałucha-Poniewiera A, Acher F, Brański P, Pilc A (December 2010). "Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems". Neuropharmacology. 59 (7–8): 627–634. doi:10.1016/j.neuropharm.2010.08.008. PMID 20713068. S2CID 5171741.

[pmid22223752-11] Goudet C, Vilar B, Courtiol T, Deltheil T, Bessiron T, Brabet I, et al. (April 2012). "A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential". FASEB Journal. 26 (4): 1682–1693. doi:10.1096/fj.11-195941. PMID 22223752. S2CID 22662090.

[pmid21688779-12] Hong SP, Liu KG, Ma G, Sabio M, Uberti MA, Bacolod MD, et al. (July 2011). "Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators". Journal of Medicinal Chemistry. 54 (14): 5070–5081. doi:10.1021/jm200290z. PMID 21688779.

[13] Hopkins CR, Niswender CM, Lewis LM, Weaver CD, Lindsley CW (2010). "Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator". Probe Reports from the NIH Molecular Libraries Program [Internet]. PMID 21433377.

[pmid19469556-14] Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon UN, Zamorano R, et al. (July 2009). "Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs)". Journal of Medicinal Chemistry. 52 (14): 4115–4118. doi:10.1021/jm9005065. PMC 2765192. PMID 19469556.

[15] Panarese JD, Engers DW, Wu YJ, Bronson JJ, Macor JE, Chun A, et al. (March 2019). "Discovery of VU2957 (Valiglurax): An mGlu₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease". ACS Medicinal Chemistry Letters. 10 (3): 255–260. doi:10.1021/acsmedchemlett.8b00426. PMC 6421540. PMID 30891122.

[pmid27441572-16] Niswender CM, Jones CK, Lin X, Bubser M, Thompson Gray A, Blobaum AL, et al. (September 2016). "Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers". ACS Chemical Neuroscience. 7 (9): 1201–1211. doi:10.1021/acschemneuro.6b00036. PMC 5073817. PMID 27441572.

[pmid27075300-17] Engers DW, Blobaum AL, Gogliotti RD, Cheung YY, Salovich JM, Garcia-Barrantes PM, et al. (September 2016). "Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4)". ACS Chemical Neuroscience. 7 (9): 1192–1200. doi:10.1021/acschemneuro.6b00035. PMC 5031509. PMID 27075300.

[pmid19097893-18] Williams R, Niswender CM, Luo Q, Le U, Conn PJ, Lindsley CW (February 2009). "Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead". Bioorganic & Medicinal Chemistry Letters. 19 (3): 962–966. doi:10.1016/j.bmcl.2008.11.104. PMC 3787871. PMID 19097893.

[pmid18664603-19] Niswender CM, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, et al. (November 2008). "Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4". Molecular Pharmacology. 74 (5): 1345–1358. doi:10.1124/mol.108.049551. PMC 2574552. PMID 18664603.

[pmid16402093-20] Watkins JC, Jane DE (January 2006). "The glutamate story". British Journal of Pharmacology. 147 (Suppl 1): S100–S108. doi:10.1038/sj.bjp.0706444. PMC 1760733. PMID 16402093.

[pmid18593581-21] Beqollari D, Kammermeier PJ (July 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". European Journal of Pharmacology. 589 (1–3): 49–52. doi:10.1016/j.ejphar.2008.06.054. PMID 18593581.

[1]

Ligands

Orthosteric

Positive allosteric modulators (PAMs)

References

Further reading