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mGlu4 receptor

Family: Metabotropic glutamate receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Allosteric Regulators
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Biologically Significant Variants
References
Gene and Protein Information
class C G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 912 6p21.3 GRM4 glutamate receptor, metabotropic 4 13,24,30,47-48
Mouse 7 832 17 A3.3 Grm4 glutamate receptor, metabotropic 4
Rat 7 912 20p12 Grm4 glutamate receptor, metabotropic 4 28,37
Structural Information Comments
The mouse sequence is provisional and has not been confirmed.
Previous and Unofficial Names
mGluR4
GPRC1D
mGlu4
glutamate receptor, metabotropic 4
metabotropic glutamate receptor 4
Database Links
ChEMBL Target 11054 (Hs), 11891 (Rn)
DrugBank Target 925 (Hs)
Ensembl ENSG00000124493 (Hs), ENSMUSG00000063239 (Mm), ENSRNOG00000000487 (Rn)
Entrez Gene 2914 (Hs), 268934 (Mm), 24417 (Rn)
GeneCards GRM4 (Hs)
GenitoUrinary Development Molecular Anatomy Project Grm4 (Mm)
HomoloGene 20230 (Hs)
Human Protein Reference Database 04978 (Hs)
InterPro Q14833 (Hs), Q68EF4 (Mm), P31423 (Rn)
KEGG Gene hsa:2914 (Hs), mmu:268934 (Mm), rno:24417 (Rn)
OMIM 604100 (Hs)
PharmGKB Gene PA28993 (Hs)
PhosphoSitePlus Q14833 (Hs), Q68EF4 (Mm), P31423 (Rn)
Protein Ontology (PRO) PRO:000008266 (Hs)
RefSeq Nucleotide NM_000841 (Hs), NM_001013385 (Mm), NM_022666 (Rn)
RefSeq Protein NP_000832 (Hs), NP_001013403 (Mm), NP_073157 (Rn)
TreeFam ENSG00000124493 (Hs), ENSMUSG00000063239 (Mm), ENSRNOG00000000487 (Rn)
UniGene Hs. 429018 (Hs)
UniProt Q14833 (Hs), Q68EF4 (Mm), P31423 (Rn)
Wikipedia mGlu4 receptor
Metabotropic glutamate receptors
Search for 3D structures on the PDB
Search by keyword: Metabotropic glutamate receptors mGlu4 receptor Search by accession number: P31423, Q14833, Q68EF4
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
[3H]AP4 Rn Full agonist 6.3 pKd 17
L-glutamic acid Rn Full agonist 4.9 – 5.5 pKi 2,17,41-42
FP0429 Hs Full agonist 7.3 – 7.4 pEC50 26
L-AP4 Hs Agonist 6.5 pEC50 48
L-SOP Hs Agonist 5.9 pEC50 48
(R,S)-4-PPG Hs Full agonist 5.3 pEC50 14-15
ACPT-I Rn Full agonist 5.1 pEC50 1
(S)-3,4-DCPG Hs Full agonist 5.1 pEC50 39
L-AP4 Rn Full agonist 6.0 – 6.4 pIC50 12,17,38,42
L-SOP Rn Full agonist 5.4 – 6.2 pIC50 12,17,38,40,42
L-CCG-I Rn Full agonist 4.3 – 5.0 pIC50 19
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
CPPG Rn Antagonist 4.6 pKi 17
MAP4 Rn Antagonist 4.6 pKi 17
MPPG Rn Antagonist 4.2 pKi 17
LY341495 Hs Antagonist 4.7 pIC50 20
View species-specific antagonist tables
Allosteric Regulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
VU0361737 Hs Positive 6.6 pEC50 11
SIB-1893 Hs Positive 6.3 – 6.8 pEC50 25
MPEP Hs Positive 6.3 – 6.6 pEC50 25
VU0155041 Hs Positive 6.1 pEC50 27
PHCCC Hs Positive 4.5 pEC50 23
Allosteric Regulator Comments
pEC50 values for MPEP and SIB-1893 were obtained in the presence of L-AP4 [25].

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

Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
References:  32,34
Tissue Distribution
Testes.
Species:  Human
Technique:  RT-PCR.
References:  36
CNS: cerebellar cortex, globus pallidus, ventral pallidum > olfactory tubercle, striatum, entopeduncular nucleus, sensory relay nuclei of the thalamus, medial and dorsolateral geniculate nuclei, substantia nigra, spinal trigeminal nucleus > neocortex layers I-III and V, piriform cortex, hippocampus, lateral and basolateral amygdaloid nuclei, superficial grey of the superior colliculus.
Species:  Mouse
Technique:  immunocytochemistry.
References:  10
CNS: cerebellum, globus pallidus > substantia nigra pars reticulata, entopeduncular nucleus, striatum, hippocampus, neocortex, thalamus.
Species:  Mouse
Technique:  immunocytochemistry.
References:  7
Retina.
Species:  Rat
Technique:  in situ hybridisation.
References:  18
Taste buds.
Species:  Rat
Technique:  in situ hybridisation.
References:  8-9,43
Pancreatic islets of Langerhans (alpha and F cells).
Species:  Rat
Technique:  RT-PCR.
References:  44
Presynaptic active zone of GABAergic axon terminals.
Species:  Rat
Technique:  immunocytochemistry.
References:  7,21
CNS: cerebellar cortex, main olfactory bulb, medial septal nucleus, mammillary nuclei > accessory olfactory bulb, olfactory tubercle, subthalamic nucleus, thalamus, pontine nuclei > neocortex, hippocampus, bed nucleus of the stria terminalis, basolateral amygdaloid nucleus, striatum, nuclues accumbens, interpeduncular nucleus, superior collicus, red nucleus, oculomotor nucleus, trochlear nucleus, periacqueductal gray.
Species:  Rat
Technique:  in situ hybridisation.
References:  29
Presynaptic active zone of excitatory axon terminals.
Species:  Rat
Technique:  immunocytochemistry.
References:  10
Retina (cell bodies of ganglion cells).
Species:  Rat
Technique:  Northern Blotting and in situ hybridisation.
References:  3
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 intracellular calcium levels in HEK cells transfected with the rat mGlu4 receptor and G15 and loaded with a calcium-sensitive dye, Fluo-4 (see comments).
Species:  Rat
Tissue:  HEK cells.
Response measured:  L-AP4-induced release of intracellular calcium.
References:  33
Measurement of intracellular calcium levels in CHO cells transfected with the human mGlu4 receptor as well as a promiscuous/chimeric G-protein comprising Gq with five amino acids from the C-terminal replaced with those from Gi3.
The calcium-mobilization assays are compatible with the fluorometric imaging plate reader formats.
Species:  Human
Tissue:  CHO cells.
Response measured:  Mobilisation of intracellular calcium.
References:  22
Measurement of cAMP levels in CHO cells transfected with the rat mGlu4 receptor.
Species:  Rat
Tissue:  CHO cells
Response measured:  Inhibition of cAMP production.
References:  38
Measurement of IP levels in HEK 293 cells transfected with the rat mGlu4 receptor and the chimeric G-protein Gqi9.
Species:  Rat
Tissue:  HEK 293 cells,
Response measured:  Stimulation of IP production.
References:  6
Functional Assay Comments
Functional responses for a series of chimeras between mGlu4/mGlu6 and mGlu4/mGlu7 led to the identification of key amino acid residues that elucidate the disperson of agonist affinities for the group III receptors mGlu4, mGluR6 and mGlu7.
Physiological Functions
In addition to the taste-mGlu4 receptor, brain-mGlu4 may be important for the sensation of glutamate taste ("umami") in rat tongue.
Species:  Rat
Tissue:  Tongue
References:  8-9,43
Conditioned taste aversion (CTA) experiments were performed to show that L-AP4 (mGlu4 agonist) mimics the taste of monosodium glutamate (MSG) ("umami" taste sense) on the rat tongue.
Species:  Rat
Tissue:  In vivo.
References:  9
Physiological Consequences of Altering Gene Expression
Agonists of mGlu4 modulate excitatory transmission in dopamine neurons and reduce neuronal degeneration in rodent Parkinsonian models.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  4,45
It was found that mGlu4 knockout mice had altered spatial learning and memory when compared against wild-type mice. These knockout mise also displaced a resistance to chemically-induced absence seizures likely mediated by alterations in glutamamte and GABA release in the thalamus. The mGlu4 knockout mice also do not show the motor stimulatory effect of ethanol.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  5,16,35,46
It was shown that mGlu4 knockout mice, while having normal spontaneous motor activities, were deficient in learning complex motor tasks.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  31
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Grm4tm1Hpn Grm4tm1Hpn/Grm4tm1Hpn
involves: 129S1/Sv * 129X1/SvJ * CD-1		 MGI:1351341  MP:0002804 abnormal motor learning PMID: 8815915 
Grm4tm1Hpn Grm4tm1Hpn/Grm4tm1Hpn
involves: 129S1/Sv * 129X1/SvJ * CD-1		 MGI:1351341  MP:0002920 decreased paired-pulse facilitation PMID: 8815915 
Grm4tm1Hpn Grm4tm1Hpn/Grm4tm1Hpn
involves: 129S1/Sv * 129X1/SvJ * CD-1		 MGI:1351341  MP:0002922 decreased post-tetanic potentiation PMID: 8815915 
Biologically Significant Variants
A variant of mGlu4(a), called mGlu4(b) has been reported that would have 135 different residues replacing the entire C-terminal tail of mGlu4(a). However, the existence of this variant has not been confirmed by RT-PCR analysis, and the human genome sequence did not reveal the presence of consensus donor and acceptor splice sites possibly responsible for the generation of this mGlu4(b) variant.
Type:  Splice variants.
Species:  Rat
References:  10,42
A truncated form of the mGlu4 receptor, taste-mGlu4, which lacks approximately 50% of the extracellular amino terminus of the full-length mGlu4 receptor, was found to impart glutamate taste ("umami") in rat taste buds. As for the mGlu4(b) variant, there is no strong data supporting the existence of this variant.
Type:  Naturally occurring mutations.
Species:  Rat
References:  8-9

REFERENCES

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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: mGlu4 receptor. Last modified on 07/02/2013. Accessed on 19/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=292.


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