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GRM1 (glutamate receptor, metabotropic 1)

Written2013-08Jairo Sierra, Suzie Chen
Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA

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HGNC (Hugo) GRM1
HGNC Alias symbGPRC1A
HGNC Alias nameprotein phosphatase 1, regulatory subunit 85
HGNC Previous nameglutamate receptor, metabotropic 1
LocusID (NCBI) 2911
Atlas_Id 43851
Location 6q24.3  [Link to chromosome band 6q24]
Location_base_pair Starts at 146029198 and ends at 146437598 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping GRM1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
BCLAF1 (6q23.3)::GRM1 (6q24.3)COL12A1 (6q13)::GRM1 (6q24.3)MEF2A (15q26.3)::GRM1 (6q24.3)
TBL1XR1 (3q26.32)::GRM1 (6q24.3)


  Figure 1. Human GRM1 has 10 exons, which are depicted by boxes and shown with the relative position to one another. Adapted from DiRaddo et al., 2013.
Description The mGluR1 gene contains 10 exons, which span a region of 409953 bp.
Transcription The transcribed matured mRNA is 6939 bps in length.


Note GRM1 encodes five alternative splice variants (1a, 1b, 1c, 1d, and 1e) (Zhu et al., 1999). All five variants contain the same N-terminal, but differ in the amino acid composition of their C-terminal domains due to the alternative splicings (DiRaddo et al., 2013).
  Figure 2. There are five human mGluR1 isoforms. The black boxes represent the seven-transmembrane domains of mGluR1. Alternative splicing of mGluR1 mRNA produces five mGluR1 isoforms each with a unique C-termini, which is highlighted by the different colors. The shortest isoform, mGluR1e, is truncated before the seven-transmembrane domains, which results in the expression of only the amino terminal fragment (Costantino and Pellicciari, 1996). Adapted from Hermans and Challiss, 2001.
Description mGluR1 is an 1194 amino acid seven-transmembrane domain G-protein coupled receptor normally expressed in neuronal and glial cells in the brain (Stephan et al., 1996; Hermans and Challiss, 2001). Its natural ligand is the excitatory neurotransmitter, L-glutamate. Structurally, mGluR1 has various domains that are necessary for its functions. The N-terminus forms two large extracellular lobes separated by a cavity where the ligand glutamate binds to and is referred to as the amino terminal domain (ATD) or "Venus Fly Trap" (O'Hara et al., 1993; Beqollari and Kammermeier, 2010). ATD is separated from the trans-membrane region of mGluR1 by a 70 amino acid cysteine rich domain (CRD), which is essential for dimerization, and activation of the receptor (Huang et al., 2011). The seven alpha-helical transmembrane domains (TMD) precede the cysteine rich region. Following the TMD is the carboxyl terminus of mGluR1, also known as the intracellular cytoplasmic tail domain (CTD). CTD is involved in modulating G-protein coupling and selectivity (Pin et al., 2003; Seebahn et al., 2013). The CTD is also the region subjected to alternative splicings, regulated by phosphorylation, and modulatory protein-protein interactions (Niswender and Conn, 2010). The CRD is consisted of three beta-pleated sheets and nine cysteine residues. CRD plays a key role in facilitating the allosteric coupling between the ATD and the TMD regions during ligand binding and receptor activation (Niswender and Conn, 2010). Upon activation of mGluR1 by glutamate, the signal induced is transmitted from the ATD through the CRDs, by way of a disulfide bridge formed between the 9th cysteine of the CRD and a cysteine residue in lobe 2 of the ATD (Rondard et al., 2006; Muto et al., 2007). As a result, a conformational change takes place that brings the C-terminal regions of the CRDs closer to one another and elicits cysteine-cysteine interaction in the e2 loop of the TMD (Muto et al., 2007). This conformational change produces a shift in the TMD to induce G-protein activation (El Moustaine et al., 2012).
Expression mGluR1 is normally expressed in the central nervous system and is activated by its natural ligand, L-glutamate (Teh and Chen, 2012a). Upon activation, mGluR1 couples to Gα/q11 proteins to induce phosphatidylinositol (4,5)-biphosphate (PIP2) hydrolysis leading to the formation of two-second messengers, inositol 1,4,5-triphosphate (IP3) and diacyglycerol (DAG) (Conn and Pin, 1997; Hermans and Challiss, 2001). These second messengers stimulate intracellular calcium release from the endoplasmic reticulum (ER) stores and activate protein kinase C (PKC), resulting in the stimulation of G-protein-independent signal transduction pathways (Hermans and Challiss, 2001; Goudet et al., 2009). Such pathways include the (MAPK) and the (Marín, et al., 2006; Shin et al., 2010).
  Figure 3. Diagram of the proposed signal transduction pathways elicited by stimulated mGluR1. Adapted from Teh and Chen, 2012b.
Localisation Cell membrane of neurons.
Function mGluR1 activation is involved in mediating neuronal excitability, synaptic plasticity, and feedback inhibition of neurotransmitter release (Speyer et al., 2012). All of which promotes learning and memory formation in the central nervous system (Hermans and Challiss, 2001).


Note Over 20 somatic missense mutations in the ligand binding and intracellular regulatory domains of mGluR1 have been identified in various tumors types (Sjöblom et al., 2006; Kan et al., 2010; Esseltine et al., 2013). A number of these mutations result in irregular mGluR1 stimulation of G protein coupling, biased ERK1/ERK2 phosphorylation, and intracellular retention in the endoplasmic reticulum (ER) (Esseltine et al., 2013). Such changes in mGluR1 signaling lead to abnormal receptor activity in numerous human cancers.

Implicated in

Entity Melanoma
Disease Melanoma is the most severe form of skin cancer and arises from the aberrant transformation of melanocytes. The most common mutations identified as drivers of melanomagenesis include B-RAF and N-RAS activating mutations as well the tumor suppressors INK4a/ARF and PTEN (Teh and Chen, 2012a).
Oncogenesis Glutamate signaling via mGluR1 has been shown to affect cell survival, cell differentiation and cell proliferation of non-neuronal tissues (Skerry and Genever, 2001; Shin et al., 2008). Chen and colleagues demonstrated the ectopic expression of mGluR1 in mouse melanocytes was sufficient to induce spontaneous metastatic melanoma development in transgenic mouse models, TG3 and Tg(Grm1)EPv (E) (Pollock et al., 2003). The ectopic expression of human mGluR1 was also detected in human melanoma cell lines and biopsy samples. To date, ~175 melanoma biopsy samples from primary to metastatic lesions have ben examined and found GRM1 mRNA and protein to be expressed in ~ 60% of the samples (Pollock et al., 2003; Namkoong et al., 2007). Moreover, expression and activation of mGluR1 in melanoma cells has been shown to activate the MAPK and P13K/AKT pathways, two of the most frequently stimulated signaling cascades in melanoma (Marín et al., 2006; Shin et al., 2010).
Entity Breast cancer (triple-negative breast cancer)
Disease Triple-negative breast cancer, are malignant tumors in breast tissue that lack estrogen receptor and progesterone receptor and amplification of the HER2 gene (Engebraaten et al., 2013).
Oncogenesis Speyer and colleagues described mGluR1 expression as a potential oncogene in mammary breast pathogenesis. They detected mGluR1 expression in multiple triple-negative breast cancer cell lines (TNBC) (Speyer et al., 2012). This group also provided evidences that the growth of TNBC cells was inhibited when mGluR1 expression was reduced by an shRNA or treatment with mGluR1 antagonist, Bay36-7620 (Speyer et al., 2012).


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Two newly identified exons in human GRM1 express a novel splice variant of metabotropic glutamate 1 receptor.
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PMID 20668451
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This paper should be referenced as such :
Sierra, J ; Chen, S
GRM1 (glutamate receptor, metabotropic 1)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(4):224-228.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)GRM1   4593
Atlas Explorer : (Salamanque)GRM1
Entrez_Gene (NCBI)GRM1    glutamate metabotropic receptor 1
AliasesGPRC1A; MGLU1; MGLUR1; PPP1R85; 
GeneCards (Weizmann)GRM1
Ensembl hg19 (Hinxton)ENSG00000152822 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000152822 [Gene_View]  ENSG00000152822 [Sequence]  chr6:146029198-146437598 [Contig_View]  GRM1 [Vega]
ICGC DataPortalENSG00000152822
TCGA cBioPortalGRM1
AceView (NCBI)GRM1
Genatlas (Paris)GRM1
SOURCE (Princeton)GRM1
Genetics Home Reference (NIH)GRM1
Genomic and cartography
GoldenPath hg38 (UCSC)GRM1  -     chr6:146029198-146437598 +  6q24.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)GRM1  -     6q24.3   [Description]    (hg19-Feb_2009)
GoldenPathGRM1 - 6q24.3 [CytoView hg19]  GRM1 - 6q24.3 [CytoView hg38]
Genome Data Viewer NCBIGRM1 [Mapview hg19]  
OMIM604473   614831   617691   
Gene and transcription
Genbank (Entrez)AB208837 AK308550 BC136280 BC143777 BC143779
RefSeq transcript (Entrez)NM_000838 NM_001114329 NM_001278064 NM_001278065 NM_001278066 NM_001278067
Consensus coding sequences : CCDS (NCBI)GRM1
Gene ExpressionGRM1 [ NCBI-GEO ]   GRM1 [ EBI - ARRAY_EXPRESS ]   GRM1 [ SEEK ]   GRM1 [ MEM ]
Gene Expression Viewer (FireBrowse)GRM1 [ Firebrowse - Broad ]
GenevisibleExpression of GRM1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2911
GTEX Portal (Tissue expression)GRM1
Human Protein AtlasENSG00000152822-GRM1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)GRM1
Human Protein Atlas [tissue]ENSG00000152822-GRM1 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed134 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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