Metabotropic glutamate receptor 4

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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. Splice variant "taste-GRM4" is involved in the perception of umami taste.[4]

## Contents

* 1 Ligands
* 1.1 Orthosteric
* 1.2 Positive allosteric modulators (PAMs)
* 2 References
* 3 Further reading

## Ligands

[edit | edit source]

### Orthosteric

[edit | edit source]

* Cinnabarinic acid, a tryptophan metabolite[5]
* LSP1-2111: agonist[6]
* LSP4-2022: agonist[7]

### Positive allosteric modulators (PAMs)

[edit | edit source]

* Foliglurax (PXT-002331, DT-1687)
* Tricyclic thiazolopyrazole derivative 22a: EC50 = 9 nM, Emax = 120%[8]
* ML-128: EC50 = 240 nM, Emax = 182%[9][10]
* VU-0418506[11][12]
* VU-001171: EC50 = 650 nM, Emax = 141%, 36-fold shift[13]
* VU-0155041: subtype-selective PAM, intrinsic allosteric agonist activity, robust in-vivo activity[14]
* PHCCC: PAM of mGluR4, negative allosteric modulator of mGluR1,[15] direct agonist at mGluR6[16]

## References

[edit | edit source]

1. ↑ Makoff A, Lelchuk R, Oxer M, Harrington K, Emson P (Apr 1996). "Molecular characterization and localization of human metabotropic glutamate receptor type 4". Brain Research. Molecular Brain Research. 37 (1–2): 239–48. doi:10.1016/0169-328X(95)00321-I. PMID 8738157.
2. ↑ Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR, Johnson BG, Schoepp DD, Belagaje RM (Jan 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.
3. ↑ 3.0 3.1 "Entrez Gene: GRM4 glutamate receptor, metabotropic 4".
4. ↑ Chaudhari N, Landin AM, Roper SD (Feb 2000). "A metabotropic glutamate receptor variant functions as a taste receptor". Nature Neuroscience. 3 (2): 113–9. doi:10.1038/72053. PMID 10649565.
5. ↑ Fazio F, Lionetto L, Molinaro G, Bertrand HO, Acher F, Ngomba RT, Notartomaso S, Curini M, Rosati O, Scarselli P, Di Marco R, Battaglia G, Bruno V, Simmaco M, Pin JP, Nicoletti F, Goudet C (May 2012). "Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors". Molecular Pharmacology. 81 (5): 643–56. doi:10.1124/mol.111.074765. PMID 22311707.
6. ↑ Wierońska JM, Stachowicz K, Pałucha-Poniewiera A, Acher F, Brański P, Pilc A (Dec 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.
7. ↑ Goudet C, Vilar B, Courtiol T, Deltheil T, Bessiron T, Brabet I, Oueslati N, Rigault D, Bertrand HO, McLean H, Daniel H, Amalric M, Acher F, Pin JP (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. doi:10.1096/fj.11-195941. PMID 22223752.
8. ↑ Hong SP, Liu KG, Ma G, Sabio M, Uberti MA, Bacolod MD, Peterson J, Zou ZZ, Robichaud AJ, Doller D (Jul 2011). "Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators". Journal of Medicinal Chemistry. 54 (14): 5070–81. doi:10.1021/jm200290z. PMID 21688779.
9. ↑ Hopkins CR, Niswender CM, Lewis LM, Weaver CD, Lindsley CW. "Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator". Probe Reports from the NIH Molecular Libraries Program [Internet]. PMID 21433377.
10. ↑ Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon UN, Zamorano R, Conn PJ, Lindsley CW, Hopkins CR (Jul 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): 4115–8. doi:10.1021/jm9005065. PMC 2765192. PMID 19469556.
11. ↑ Niswender CM, Jones CK, Lin X, Bubser M, Thompson Gray A, Blobaum AL, Engers DW, Rodriguez AL, Loch MT, Daniels JS, Lindsley CW, Hopkins CR, Javitch JA, Conn PJ (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 Chem Neurosci. 7: 1201–11. doi:10.1021/acschemneuro.6b00036. PMID 27441572.
12. ↑ Engers DW, Blobaum AL, Gogliotti RD, Cheung YY, Salovich JM, Garcia-Barrantes PM, Daniels JS, Morrison R, Jones CK, Soars MG, Zhuo X, Hurley J, Macor JE, Bronson JJ, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR (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 Chem Neurosci. 7: 1192–200. doi:10.1021/acschemneuro.6b00035. PMID 27075300.
13. ↑ Williams R, Niswender CM, Luo Q, Le U, Conn PJ, Lindsley CW (Feb 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): 962–6. doi:10.1016/j.bmcl.2008.11.104. PMC 3787871. PMID 19097893.
14. ↑ Niswender CM, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, Rodriguez AL, Marlo JE, de Paulis T, Thompson AD, Days EL, Nalywajko T, Austin CA, Williams MB, Ayala JE, Williams R, Lindsley CW, Conn PJ (Nov 2008). "Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4". Molecular Pharmacology. 74 (5): 1345–58. doi:10.1124/mol.108.049551. PMC 2574552. PMID 18664603.
15. ↑ Watkins JC, Jane DE (Jan 2006). "The glutamate story". British Journal of Pharmacology. 147 Suppl 1: S100–8. doi:10.1038/sj.bjp.0706444. PMC 1760733. PMID 16402093.
16. ↑ Beqollari D, Kammermeier PJ (Jul 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.

## Further reading

[edit | edit source]

* Flor PJ, Lukic S, Rüegg D, Leonhardt T, Knöpfel T, Kuhn R (Feb 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, Heng HH, Belloni E, Tsui LC (Jan 1996). "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, Parmentier ML, Restituito S, Bockaert J, Pin JP (Oct 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): 923–30. PMID 8863838.
* Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi-Baez L, Ogryzko V, Avantaggiati ML, Pestell RG (Jul 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): 20853–60. 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". Cytogenetics and Cell Genetics. 88 (3–4): 210. doi:10.1159/000015551. PMID 10828590.
* Ohtsuki T, Toru M, Arinami T (Jun 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.
* Erdemir T, Bilican B, Oncel D, Goding CR, Yavuzer U (Jan 2002). "DNA damage-dependent interaction of the nuclear matrix protein C1D with Translin-associated factor X (TRAX)". Journal of Cell Science. 115 (Pt 1): 207–16. PMID 11801738.
* Collard CD, Park KA, Montalto MC, Alapati S, Buras JA, Stahl GL, Colgan SP (Apr 2002). "Neutrophil-derived glutamate regulates vascular endothelial barrier function". The Journal of Biological Chemistry. 277 (17): 14801–11. doi:10.1074/jbc.M110557200. PMID 11847215.
* Enz R (Mar 2002). "The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7". FEBS Letters. 514 (2–3): 184–8. doi:10.1016/S0014-5793(02)02361-X. PMID 11943148.
* Gaughan L, Logan IR, Cook S, Neal DE, Robson CN (Jul 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): 25904–13. doi:10.1074/jbc.M203423200. PMID 11994312.
* Iacovelli L, Capobianco L, Iula M, Di Giorgi Gerevini V, Picascia A, Blahos J, Melchiorri D, Nicoletti F, De Blasi A (May 2004). "Regulation of mGlu4 metabotropic glutamate receptor signaling by type-2 G-protein coupled receptor kinase (GRK2)". Molecular Pharmacology. 65 (5): 1103–10. doi:10.1124/mol.65.5.1103. PMID 15102938.
* Hermit MB, Greenwood JR, Bräuner-Osborne H (Aug 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): 34811–7. doi:10.1074/jbc.M404109200. PMID 15184361.
* Yoo BC, Jeon E, Hong SH, Shin YK, Chang HJ, Park JG (Jun 2004). "Metabotropic glutamate receptor 4-mediated 5-Fluorouracil resistance in a human colon cancer cell line". Clinical Cancer Research. 10 (12 Pt 1): 4176–84. 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): 3288–95. doi:10.1158/1078-0432.CCR-04-1912. PMID 15867225.
* Mathiesen JM, Ramirez MT (Jun 2006). "The metabotropic glutamate receptor 4 is internalized and desensitized upon protein kinase C activation". British Journal of Pharmacology. 148 (3): 279–90. doi:10.1038/sj.bjp.0706733. PMC 1751557. PMID 16582932.
* Iacovelli L, Arcella A, Battaglia G, Pazzaglia S, Aronica E, Spinsanti P, Caruso A, De Smaele E, Saran A, Gulino A, D'Onofrio M, Giangaspero F, Nicoletti F (Aug 2006). "Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas". The Journal of Neuroscience. 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.

* v
* t
* e

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
* GHB receptor
* Histamine
* H1
* H2
* H3
* H4
* Melatonin (1A
* 1B
* 1C)
* TAAR (1
* 2
* 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)
* Hydroxycarboxylic acids
* 1
* 2
* 3
* Lysophosphatidic acid (1
* 2
* 3
* 4
* 5
* 6)
* Lysophospholipid (1
* 2
* 3
* 4
* 5
* 6
* 7
* 8)
* 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)
* 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

| Adhesion|

* ADGRG (1
* 2
* 3
* 4
* 5
* 6
* 7)

|

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
* 7
* 8
* 9
* 10
* 13
* 14
* 16
* 19
* 20
* 30
* 31
* 38
* 39
* 40
* 41
* 42
* 43
* 45
* 46
* 50
* 60
* Vomeronasal receptor)

|

Other|

* Calcium-sensing receptor
* GABAB (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

* v
* t
* e

Metabotropic glutamate receptor modulators

Group I|

| mGluR1|

* Agonists: ACPD
* DHPG
* Glutamate
* Ibotenic acid
* Quisqualic acid
* Ro01-6128
* Ro67-4853
* Ro67-7476
* VU-71
* Theanine

* Antagonists: BAY 36-7620
* CPCCOEt
* Cyclothiazide
* LY-367,385
* LY-456,236
* MCPG
* NPS-2390

|

mGluR5|

* Agonists: ACPD
* ADX-47273
* CDPPB
* CHPG
* DFB
* DHPG
* Glutamate
* Ibotenic acid
* Quisqualic acid
* VU-1545

* Antagonists: CTEP
* DMeOB
* LY-344,545
* Mavoglurant
* MCPG
* NPS-2390
* Remeglurant
* SIB-1757
* SIB-1893; Negative allosteric modulators: Basimglurant
* Dipraglurant
* Fenobam
* GRN-529
* MPEP
* MTEP
* Raseglurant

Group II|

| mGluR2|

* Agonists: BINA
* CBiPES
* DCG-IV
* Eglumegad
* Glutamate
* Ibotenic acid
* LY-379,268
* LY-404,039 (pomaglumetad)
* LY-487,379
* LY-566,332
* MGS-0028
* Pomaglumetad methionil (LY-2140023)
* Talaglumetad; Positive allosteric modulators: JNJ-40411813 (ADX-71149)

* Antagonists: APICA
* CECXG
* EGLU
* HYDIA
* LY-307,452
* LY-341,495
* MCPG
* MGS-0039
* PCCG-4; Negative allosteric modulators: Decoglurant
* RO4491533

|

mGluR3|

* Agonists: CBiPES
* DCG-IV
* Eglumegad
* Glutamate
* Ibotenic acid
* LY-379,268
* LY-404,039 (pomaglumetad)
* LY-487,379
* MGS-0028
* Pomaglumetad methionil (LY-2140023)
* Talaglumetad

* Antagonists: APICA
* CECXG
* EGLU
* HYDIA
* LY-307,452
* LY-341,495
* MCPG
* MGS-0039; Negative allosteric modulators: Decoglurant
* RO4491533

Group III|

| mGluR4|

* Agonists: Glutamate
* L-AP4
* PHCCC
* VU-001,171
* VU-0155,041; Positive allosteric modulators: Foliglurax
* MPEP

* Antagonists: CPPG
* MAP4
* MPPG
* MSOP
* MTPG
* UBP-1112

|

mGluR6|

* Agonists: Glutamate
* L-AP4

* Antagonists: CPPG
* MAP4
* MPPG
* MSOP
* MTPG
* UBP-1112

mGluR7|

* Agonists: AMN082
* Glutamate
* L-AP4

* Antagonists: CPPG
* MAP4
* MMPIP
* MPPG
* MSOP
* MTPG
* UBP-1112

mGluR8|

* Agonists: DCPG
* Glutamate
* L-AP4

* Antagonists: CPPG
* MAP4
* MPPG
* MSOP
* MTPG
* UBP-1112

See also: Receptor/signaling modulators • Ionotropic glutamate receptor modulators • Glutamate metabolism/transport modulators
*[v]: View this template
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*[mGluR1]: Metabotropic glutamate receptor 1
*[mGluR5]: Metabotropic glutamate receptor 5
*[mGluR2]: Metabotropic glutamate receptor 2
*[mGluR3]: Metabotropic glutamate receptor 3
*[mGluR4]: Metabotropic glutamate receptor 4
*[mGluR6]: Metabotropic glutamate receptor 6
*[mGluR7]: Metabotropic glutamate receptor 7
*[mGluR8]: Metabotropic glutamate receptor 8