Metabotropic glutamate receptor 4

Glutamate receptor, metabotropic 4

Identifiers

GRM4; GPRC1D; MGC177594; MGLUR4; mGlu4

External IDs

OMIM: 604100 MGI: 1351341 HomoloGene: 20230 IUPHAR: mGlu₄ GeneCards: GRM4 Gene

Gene Ontology
Molecular function	• receptor activity • G-protein coupled receptor activity • glutamate receptor activity
Cellular component	• intracellular • plasma membrane • integral to plasma membrane • cytoplasmic vesicle
Biological process	• activation of MAPK activity • G-protein coupled receptor protein signaling pathway • inhibition of adenylate cyclase activity by metabotropic glutamate receptor signaling pathway • synaptic transmission • neurotransmitter secretion • positive regulation of MAPKKK cascade • neuroprotection
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 6:
33.99 – 34.12 Mb

Chr 17:
27.56 – 27.65 Mb

PubMed search

[1]

[2]

Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.^[1]^[2]^[3]

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.^[3] Activation of GRM4 has potential therapeutic benefits in the treatment of parkinson's disease. "Taste-GRM4" is involved in the perception of umami.

1 Ligands
- 1.1 Orthosteric
- 1.2 Positive allosteric modulators (PAMs)
2 References
3 External links
4 Further reading

Ligands

Orthosteric

LSP1-2111^[4], LSP1-3081: agonists

Positive allosteric modulators (PAMs)

Tricyclic thiazolopyrazole derivative 22a: EC₅₀ = 9 nM, E_max = 120%^[5]
ML-128: EC₅₀ = 240 nM, E_max = 182%^[6]^[7]
VU-001171: EC₅₀ = 650 nM, E_max = 141%, 36-fold shift^[8]
VU-0155041: subtype-selective PAM, intrinsic allosteric agonist activity, robust in-vivo activity^[9]
PHCCC: PAM of mGluR4, negative allosteric modulator of mGluR1,^[10] direct agonist at mGluR6^[11]

References

^ Makoff A, Lelchuk R, Oxer M, Harrington K, Emson P (Dec 1996). "Molecular characterization and localization of human metabotropic glutamate receptor type 4". Brain Res Mol Brain Res 37 (1-2): 239–48. doi:10.1016/0169-328X(95)00321-I. PMID 8738157.
^ Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR Jr, Johnson BG, Schoepp DD, Belagaje RM (Apr 1998). "Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells". Brain Res Mol Brain Res 53 (1-2): 88–97. doi:10.1016/S0169-328X(97)00277-5. PMID 9473604.
^ ^a ^b "Entrez Gene: GRM4 glutamate receptor, metabotropic 4". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2914.
^ 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): 627–34. doi:10.1016/j.neuropharm.2010.08.008. PMID 20713068.
^ Hong SP, Liu KG, Ma G, et al. (July 2011). "Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators". J. Med. Chem. 54 (14): 5070–81. doi:10.1021/jm200290z. PMID 21688779.
^ Hopkins CR, Niswender CM, Lewis LM, Weaver CD, Lindsley CW. PMID 21433377.
^ Engers DW, Niswender CM, Weaver CD, 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)". J. Med. Chem. 52 (14): 4115–8. doi:10.1021/jm9005065. PMC 2765192. PMID 19469556. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2765192.
^ Williams R, Niswender CM, Luo Q, Le U, Conn PJ, Lindsley CW (2009). "Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead". Bioorg. Med. Chem. Lett. 19 (3): 962–6. doi:10.1016/j.bmcl.2008.11.104. PMID 19097893.
^ Niswender CM, Johnson KA, Weaver CD, et al. (2008). "Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4". Mol. Pharmacol. 74 (5): 1345–58. doi:10.1124/mol.108.049551. PMC 2574552. PMID 18664603. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2574552.
^ Watkins JC, Jane DE (2006). "The glutamate story". British journal of pharmacology 147 Suppl 1: S100–8. doi:10.1038/sj.bjp.0706444. PMC 1760733. PMID 16402093. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1760733.
^ 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". European journal of pharmacology 589 (1-3): 49–52. doi:10.1016/j.ejphar.2008.06.054. PMID 18593581.

External links

"Metabotropic Glutamate Receptors: mGlu₄". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2274.

Flor PJ, Lukic S, Rüegg D, et al. (1995). "Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 4.". Neuropharmacology 34 (2): 149–55. doi:10.1016/0028-3908(94)00149-M. PMID 7617140.
Scherer SW, Duvoisin RM, Kuhn R, et al. (1997). "Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q.". Genomics 31 (2): 230–3. doi:10.1006/geno.1996.0036. PMID 8824806.
Gomeza J, Mary S, Brabet I, et al. (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.". Mol. Pharmacol. 50 (4): 923–30. PMID 8863838.
Fu M, Wang C, Reutens AT, et al. (2000). "p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation.". J. Biol. Chem. 275 (27): 20853–60. 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.". Cytogenet. Cell Genet. 88 (3-4): 210. doi:10.1159/000015551. PMID 10828590.
Ohtsuki T, Toru M, Arinami T (2002). "Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia.". Psychiatr. Genet. 11 (2): 79–83. doi:10.1097/00041444-200106000-00004. PMID 11525421.
Erdemir T, Bilican B, Oncel D, et al. (2002). "DNA damage-dependent interaction of the nuclear matrix protein C1D with Translin-associated factor X (TRAX).". J. Cell. Sci. 115 (Pt 1): 207–16. PMID 11801738.
Collard CD, Park KA, Montalto MC, et al. (2002). "Neutrophil-derived glutamate regulates vascular endothelial barrier function.". J. Biol. Chem. 277 (17): 14801–11. doi:10.1074/jbc.M110557200. PMID 11847215.
Enz R (2002). "The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7.". FEBS Lett. 514 (2-3): 184–8. doi:10.1016/S0014-5793(02)02361-X. PMID 11943148.
Gaughan L, Logan IR, Cook S, et al. (2002). "Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor.". J. Biol. Chem. 277 (29): 25904–13. doi:10.1074/jbc.M203423200. PMID 11994312.
Mungall AJ, Palmer SA, Sims SK, et al. (2003). "The DNA sequence and analysis of human chromosome 6.". Nature 425 (6960): 805–11. doi:10.1038/nature02055. PMID 14574404.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
Iacovelli L, Capobianco L, Iula M, et al. (2004). "Regulation of mGlu4 metabotropic glutamate receptor signaling by type-2 G-protein coupled receptor kinase (GRK2).". Mol. Pharmacol. 65 (5): 1103–10. doi:10.1124/mol.65.5.1103. PMID 15102938.
Hermit MB, Greenwood JR, Bräuner-Osborne H (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.". J. Biol. Chem. 279 (33): 34811–7. doi:10.1074/jbc.M404109200. PMID 15184361.
Yoo BC, Jeon E, Hong SH, et al. (2005). "Metabotropic glutamate receptor 4-mediated 5-Fluorouracil resistance in a human colon cancer cell line.". Clin. Cancer Res. 10 (12 Pt 1): 4176–84. doi:10.1158/1078-0432.CCR-1114-03. PMID 15217955.
Chang HJ, Yoo BC, Lim SB, et al. (2005). "Metabotropic glutamate receptor 4 expression in colorectal carcinoma and its prognostic significance.". Clin. Cancer Res. 11 (9): 3288–95. doi:10.1158/1078-0432.CCR-04-1912. PMID 15867225.
Mathiesen JM, Ramirez MT (2006). "The metabotropic glutamate receptor 4 is internalized and desensitized upon protein kinase C activation.". Br. J. Pharmacol. 148 (3): 279–90. doi:10.1038/sj.bjp.0706733. PMC 1751557. PMID 16582932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1751557.
Iacovelli L, Arcella A, Battaglia G, et al. (2006). "Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas.". J. Neurosci. 26 (32): 8388–97. doi:10.1523/JNEUROSCI.2285-06.2006. PMID 16899734.

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

Cell surface receptor: G protein-coupled receptors

Class A:
Rhodopsin like

Neurotransmitter

Adrenergic	α1 (A, B, D) · α2 (A, B, C) · β1 · β2 · β3

Purinergic	Adenosine (A1, A2A, A2B, A3) · P2Y (1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)

Serotonin	(all but 5-HT3) 5-HT1 (A, B, D, E, F) · 5-HT2 (A, B, C) · 5-HT (4, 5A, 6, 7)

Other	Acetylcholine (M1, M2, M3, M4, M5) · Dopamine (D1, D2, D3, D4, D5) · Histamine (H1, H2, H3, H4) · Melatonin (1A, 1B, 1C) · TAAR (1, 2, 3, 5, 6, 8, 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1, 2) · LTB4 (1, 2) · FPRL1 · OXE · Prostaglandin (DP (1, 2), EP (1, 2, 3, 4), FP) · Prostacyclin · Thromboxane

Other	Bile acid · Cannabinoid (CB1, CB2, GPR (18, 55, 119)) · EBI2 · Estrogen · Free fatty acid (1, 2, 3, 4) · Lactate · Lysophosphatidic acid (1, 2, 3, 4, 5, 6) · Lysophospholipid (1, 2, 3, 4, 5, 6, 7, 8) · Niacin (1, 2) · Oxoglutarate · PAF · Sphingosine-1-phosphate (1, 2, 3, 4, 5) · Succinate

Peptide

Neuropeptide	B/W (1, 2) · FF (1, 2) · S · Y (1, 2, 4, 5) · Neuromedin (B, U (1, 2)) · Neurotensin (1, 2)

Other	Anaphylatoxin (C3a, C5a) · Angiotensin (1, 2) · Apelin · Bombesin (BRS3, GRPR, NMBR) · Bradykinin (B1, B2) · Chemokine · Cholecystokinin (A, B) · Endothelin (A, B) · Formyl peptide (1, 2, 3) · FSH · Galanin (1, 2, 3) · GHB receptor · Gonadotropin-releasing hormone (1, 2) · Ghrelin · Kisspeptin · Luteinizing hormone/choriogonadotropin · MAS (1, 1L, D, E, F, G, X1, X2, X3, X4) · Melanocortin (1, 2, 3, 4, 5) · MCHR (1, 2) · Motilin · Opioid (Delta, Kappa, Mu, Nociceptin & Zeta, but not Sigma) · Orexin (1, 2) · Oxytocin · Prokineticin (1, 2) · Prolactin-releasing peptide · Relaxin (1, 2, 3, 4) · Somatostatin (1, 2, 3, 4, 5) · Tachykinin (1, 2, 3) · Thyrotropin · Thyrotropin-releasing hormone · Urotensin-II · Vasopressin (1A, 1B, 2)

Miscellaneous

Orphan	GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 81, 82, 83, 84, 85, 87, 88, 92, 101, 103, 109A, 109B, 119, 120, 132, 135, 137B, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 173, 174, 176, 177, 182, 183)

Other	Adrenomedullin · Olfactory · Opsin (3, 4, 5, 1LW, 1MW, 1SW, RGR, RRH) · Protease-activated (1, 2, 3, 4) · SREB (1, 2, 3)

Class B: Secretin like

Orphan	GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 155, 157)

Other	Brain-specific angiogenesis inhibitor (1, 2, 3) · Cadherin (1, 2, 3) · Calcitonin · CALCRL · CD97 · Corticotropin-releasing hormone (1, 2) · EMR (1, 2, 3) · Glucagon (GR, GIPR, GLP1R, GLP2R) · Growth hormone releasing hormone · PACAPR1 · GPR · Latrophilin (1, 2, 3, ELTD1) · Methuselah-like proteins · Parathyroid hormone (1, 2) · Secretin · Vasoactive intestinal peptide (1, 2)

Class C: Metabotropic
glutamate / pheromone

Taste	TAS1R (1, 2, 3) · TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 19, 20, 30, 31, 38, 39, 40, 41, 42, 43, 45, 46, 50)

Other	Calcium-sensing receptor · GABA B (1, 2) · Glutamate receptor (Metabotropic glutamate (1, 2, 3, 4, 5, 6, 7, 8)) · GPRC6A · GPR (156, 158, 179) · RAIG (1, 2, 3, 4)

Class F:
Frizzled / Smoothened

Frizzled	Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

Smoothened	Smoothened

B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)