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    GRM4 glutamate metabotropic receptor 4 [ Homo sapiens (human) ]

    Gene ID: 2914, updated on 2-Nov-2024

    Summary

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    Official Symbol
    GRM4provided by HGNC
    Official Full Name
    glutamate metabotropic receptor 4provided by HGNC
    Primary source
    HGNC:HGNC:4596
    See related
    Ensembl:ENSG00000124493 MIM:604100; AllianceGenome:HGNC:4596
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    mGlu4; GPRC1D; MGLUR4
    Summary
    L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]
    Expression
    Low expression observed in reference dataset See more
    Orthologs
    mouse all
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    Genomic context

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    See GRM4 in Genome Data Viewer
    Location:
    6p21.31
    Exon count:
    15
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 6 NC_000006.12 (34018643..34155622, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 6 NC_060930.1 (33839943..33979214, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 6 NC_000006.11 (33986420..34123399, complement)

    Chromosome 6 - NC_000006.12Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC124901308 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:33922205-33922705 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:33925615-33926355 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:33926356-33927095 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:33961394-33962166 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:33967681-33968182 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr6:33973921-33974803 Neighboring gene microRNA 1275 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:33993583-33994310 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 17058 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:33999095-33999617 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 24375 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:34015538-34016092 Neighboring gene NANOG-H3K4me1 hESC enhancer GRCh37_chr6:34016093-34016646 Neighboring gene NANOG-H3K4me1 hESC enhancer GRCh37_chr6:34016647-34017200 Neighboring gene Sharpr-MPRA regulatory region 5466 Neighboring gene Sharpr-MPRA regulatory region 4098 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr6:34031248-34031829 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:34044839-34045669 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:34046709-34047454 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:34050139-34050978 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:34050979-34051818 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:34074290-34074790 Neighboring gene MPRA-validated peak5759 silencer Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr6:34087978-34088766 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr6:34099315-34100141 Neighboring gene Sharpr-MPRA regulatory region 15272 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:34121411-34122268 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 17059 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 24376 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 24377 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 24378 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 24379 Neighboring gene keratin 18 pseudogene 9 Neighboring gene CYCS pseudogene 55

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Metabotropic glutamate receptor 4 expression in colorectal carcinoma and its prognostic significance. Chang HJ, et al. Clin Cancer Res, 2005 May 1. PMID 15867225
    2. Role of GRM4 in idiopathic generalized epilepsies analysed by genetic association and sequence analysis. Muhle H, et al. Epilepsy Res, 2010 May. PMID 20338729
    3. A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation. Saxe JP, et al. Chem Biol, 2007 Sep. PMID 17884634, Free PMC Article
    4. Association of the GRM4 gene variants with juvenile myoclonic epilepsy in an Indian population. Parihar R, et al. J Genet, 2014 Apr. PMID 24840839
    5. GRM4 gene polymorphism is associated with susceptibility and prognosis of osteosarcoma in a Chinese Han population. Jiang C, et al. Med Oncol, 2014 Jul. PMID 24984297, Free PMC Article

    See all (53) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4.
      Title: Structures of G(i)-bound metabotropic glutamate receptors mGlu2 and mGlu4.
    2. Regulation and functional consequences of mGlu4 RNA editing.
      Title: Regulation and functional consequences of mGlu(4) RNA editing.
    3. Association between the group III metabotropic glutamate receptor gene polymorphisms and attention-deficit/hyperactivity disorder and functional exploration of risk loci.
      Title: Association between the group III metabotropic glutamate receptor gene polymorphisms and attention-deficit/hyperactivity disorder and functional exploration of risk loci.
    4. Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23.
      Title: Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23.
    5. This is the evidence supporting the interaction between GRM4 and CBX4, which could inhibit the malignant behavior of osteosarcoma cells through the GRM4/CBX4/HIF-1alpha signaling pathway
      Title: GRM4 inhibits the proliferation, migration, and invasion of human osteosarcoma cells through interaction with CBX4.
    6. Ectopic expression of glutamate metabotropic receptors (GRM) is correlated with better prognosis of breast cancer (BC)patients. Overexpression of GRM4 significantly inhibits cell proliferation, migration and invasion capacity in BC cell line MDA-MB-231. Overexpression of miR-328-3p and miR-370-3p counteracts the inhibitory effect of GRM4-induced cell proliferation, migration and invasion.
      Title: Glutamate metabotropic receptor 4 (GRM4) inhibits cell proliferation, migration and invasion in breast cancer and is regulated by miR-328-3p and miR-370-3p.
    7. Results supply an important evidence that mGluR4 is expressed in prenatal human cerebrum, and main kinds of cells related to neurogenesis are involved in its expression.
      Title: The developmental expression of metabotropic glutamate receptor 4 in prenatal human frontal lobe and neurogenesis regions.
    8. We identified multiple novel associations of genetic variants in GRM3, GRM4, and GRM5 with the risk and the survival of renal cell carcinoma (RCC). These relationships were supported by gene expression profiles obtained using bioinformatics analysis. Specifically, the expression of GRM4 and GRM5 showed an increasing trend in RCC tissues, compared to that in normal tissue, whereas GRM3 was downregulated in RCC.
      Title: Clinical significance of glutamate metabotropic receptors in renal cell carcinoma risk and survival.
    9. EGR1 and CTCF are probably involved in the transcriptional regulation of GRM4, which participates in the progress of osteosarcoma by interacting with chemokines and their receptors.
      Title: To Explore the Mechanism of the GRM4 Gene in Osteosarcoma by RNA Sequencing and Bioinformatics Approach.
    10. Results suggest that variant rs2229901 of glutamate receptor 4 is associated with major depressive disorder risk. This variant probably impacts the interaction between GRM4 and miR-1202.
      Title: A genetic variant in miRNA binding site of glutamate receptor 4, metabotropic (GRM4) is associated with increased risk of major depressive disorder.
    Submit: New GeneRIF Correction See all GeneRIFs (27)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    EBI GWAS Catalog

    Description
    Genome-wide association study identifies two susceptibility loci for osteosarcoma.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    HIV-1 interactions

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    Protein interactions

    Protein Gene Interaction Pubs
    Tat tat The gene expression of GRM4 is significantly upregulated in both clade B and clade C Tat treated SK-N-MC neuroblastoma cells PubMed

    Go to the HIV-1, Human Interaction Database

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ98710, MGC177594

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables G protein-coupled receptor activity IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    enables adenylate cyclase inhibiting G protein-coupled glutamate receptor activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables glutamate receptor activity IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in G protein-coupled glutamate receptor signaling pathway IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in chemical synaptic transmission TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in neurotransmitter secretion TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in positive regulation of MAPK cascade IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in regulation of neuron apoptotic process TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in regulation of synaptic transmission, glutamatergic IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    Component Evidence Code Pubs
    located_in cytoplasmic vesicle IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    is_active_in plasma membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in plasma membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in plasma membrane TAS
    Traceable Author Statement
    more info
    		  
    located_in presynapse IEA
    Inferred from Electronic Annotation
    more info
    		  

    General protein information

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    Preferred Names
    metabotropic glutamate receptor 4
    Names
    glutamate receptor, metabotropic 4

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_029677.3 RefSeqGene

      Range
      14536..141980
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_000841.4 → NP_000832.1  metabotropic glutamate receptor 4 isoform 1 precursor

      See identical proteins and their annotated locations for NP_000832.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).
      Source sequence(s)
      AL590403, BM683737, DA094245, X80818
      Consensus CDS
      CCDS4787.1
      UniProtKB/Swiss-Prot
      B3KVL9, B7Z1T9, B7Z1U6, F5GXM5, Q14833, Q5SZ84, Q6ZMQ2
      UniProtKB/TrEMBL
      A1L4F9, A8K0F9, A8K0G9
      Related
      ENSP00000440556.1, ENST00000538487.7
      Conserved Domains (3) summary
      pfam07562
      Location:517 → 566
      NCD3G; Nine Cysteines Domain of family 3 GPCR
      cd15452
      Location:586 → 912
      7tmC_mGluR4; metabotropic glutamate receptor 4 in group 3, member of the class C family of seven-transmembrane G protein-coupled receptors
      cl10011
      Location:47 → 508
      Periplasmic_Binding_Protein_Type_1; Type 1 periplasmic binding fold superfamily

    2. NM_001256809.3 → NP_001243738.1  metabotropic glutamate receptor 4 isoform 2

      See identical proteins and their annotated locations for NP_001243738.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) differs in the 5' UTR and coding sequence, and lacks an alternate in-frame exon compared to variant 1. The resulting isoform (2) has a shorter and distinct N-terminus and lacks an alternate internal segment compared to isoform 1.
      Source sequence(s)
      AK131536, AL590403, BM683737
      Consensus CDS
      CCDS59012.1
      UniProtKB/Swiss-Prot
      Q14833
      Related
      ENSP00000363292.3, ENST00000374177.7
      Conserved Domains (4) summary
      pfam00003
      Location:483 → 728
      7tm_3; 7 transmembrane sweet-taste receptor of 3 GCPR
      pfam01094
      Location:103 → 361
      ANF_receptor; Receptor family ligand binding region
      pfam07562
      Location:401 → 448
      NCD3G; Nine Cysteines Domain of family 3 GPCR
      cl10011
      Location:104 → 392
      Periplasmic_Binding_Protein_Type_1; Type 1 periplasmic binding fold superfamily

    3. NM_001256811.3 → NP_001243740.1  metabotropic glutamate receptor 4 isoform 4 precursor

      See identical proteins and their annotated locations for NP_001243740.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) lacks an alternate in-frame exon compared to variant 1. The resulting isoform (4) has the same N- and C-termini but is shorter compared to isoform 1.
      Source sequence(s)
      AK131536, AK312300, AL590403, BC144057, BM683737
      Consensus CDS
      CCDS75432.1
      UniProtKB/TrEMBL
      A8K0F9, A8K0G9, B7ZLU9
      Related
      ENSP00000363296.4, ENST00000374181.8
      Conserved Domains (4) summary
      pfam00003
      Location:552 → 797
      7tm_3; 7 transmembrane sweet-taste receptor of 3 GCPR
      pfam01094
      Location:77 → 430
      ANF_receptor; Receptor family ligand binding region
      pfam07562
      Location:470 → 517
      NCD3G; Nine Cysteines Domain of family 3 GPCR
      cl10011
      Location:47 → 461
      Periplasmic_Binding_Protein_Type_1; Type 1 periplasmic binding fold superfamily

    4. NM_001256812.2 → NP_001243741.1  metabotropic glutamate receptor 4 isoform 5

      See identical proteins and their annotated locations for NP_001243741.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) differs in the 5' UTR and coding sequence compared to variant 1. The resulting isoform (5) has a shorter and distinct N-terminus compared to isoform 1.
      Source sequence(s)
      AK131536, AK293913, AL590403, BM683737
      Consensus CDS
      CCDS59011.1
      UniProtKB/TrEMBL
      A8K0G9
      Related
      ENSP00000437730.1, ENST00000544773.6
      Conserved Domains (3) summary
      pfam07562
      Location:348 → 397
      NCD3G; Nine Cysteines Domain of family 3 GPCR
      cd15452
      Location:417 → 743
      7tmC_mGluR4; metabotropic glutamate receptor 4 in group 3, member of the class C family of seven-transmembrane G protein-coupled receptors
      cl10011
      Location:4 → 339
      Periplasmic_Binding_Protein_Type_1; Type 1 periplasmic binding fold superfamily

    5. NM_001256813.3 → NP_001243742.1  metabotropic glutamate receptor 4 isoform 6

      See identical proteins and their annotated locations for NP_001243742.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (6) differs in the 5' UTR and coding sequence compared to variant 1. The resulting isoform (6) has a shorter and distinct N-terminus compared to isoform 1.
      Source sequence(s)
      AK122982, AK131536, AL590403, BM683737
      Consensus CDS
      CCDS59010.1
      UniProtKB/TrEMBL
      A8K0G9
      Related
      ENSP00000477466.1, ENST00000609222.5
      Conserved Domains (4) summary
      pfam00003
      Location:466 → 711
      7tm_3; 7 transmembrane sweet-taste receptor of 3 GCPR
      pfam01094
      Location:39 → 344
      ANF_receptor; Receptor family ligand binding region
      pfam07562
      Location:384 → 431
      NCD3G; Nine Cysteines Domain of family 3 GPCR
      cl10011
      Location:40 → 375
      Periplasmic_Binding_Protein_Type_1; Type 1 periplasmic binding fold superfamily

    6. NM_001282847.2 → NP_001269776.1  metabotropic glutamate receptor 4 isoform 8

      See identical proteins and their annotated locations for NP_001269776.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (8) uses an alternate 5' structure and thus differs in the 5' UTR and 5' coding region compared to variant 1. These differences cause translation initiation at a downstream AUG and result in an isoform (8) with a shorter N-terminus, compared to isoform 1.
      Source sequence(s)
      AK131536, AK312300, AL590403, BM683737
      UniProtKB/TrEMBL
      A8K0J8, B3KX58
      Conserved Domains (3) summary
      pfam07562
      Location:209 → 258
      NCD3G; Nine Cysteines Domain of family 3 GPCR
      cd15452
      Location:278 → 604
      7tmC_mGluR4; metabotropic glutamate receptor 4 in group 3, member of the class C family of seven-transmembrane G protein-coupled receptors
      cl10011
      Location:1 → 200
      Periplasmic_Binding_Protein_Type_1; Type 1 periplasmic binding fold superfamily

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000006.12 Reference GRCh38.p14 Primary Assembly

      Range
      34018643..34155622 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060930.1 Alternate T2T-CHM13v2.0

      Range
      33839943..33979214 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Suppressed Reference Sequence(s)

    The following Reference Sequences have been suppressed. Explain

    1. NM_001256810.1: Suppressed sequence

      Description
      NM_001256810.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.

    2. NM_001256814.1: Suppressed sequence

      Description
      NM_001256814.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q14833.1 GenPept UniProtKB/Swiss-Prot:Q14833

    Gene LinkOut

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