GRM1 (glutamate receptor, metabotropic 1)

2013-08-01   Jairo 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




Atlas Image
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.


The mGluR1 gene contains 10 exons, which span a region of 409953 bp.


The transcribed matured mRNA is 6939 bps in length.



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).
Atlas Image
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.


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" (OHara 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).


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 mitogen activated protein kinase pathway (MAPK) and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway (Marín, et al., 2006; Shin et al., 2010).
Atlas Image
Figure 3. Diagram of the proposed signal transduction pathways elicited by stimulated mGluR1. Adapted from Teh and Chen, 2012b.


Cell membrane of neurons.


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).



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 name
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).
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 name
Breast cancer (triple-negative breast cancer)
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).
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).


Pubmed IDLast YearTitleAuthors
204631922010Venus fly trap domain of mGluR1 functions as a dominant negative against group I mGluR signaling.Beqollari D et al
91312521997Pharmacology and functions of metabotropic glutamate receptors.Conn PJ et al
88317651996Homology modeling of metabotropic glutamate receptors. (mGluRs) structural motifs affecting binding modes and pharmacological profile of mGluR1 agonists and competitive antagonists.Costantino G et al
234816972013Two newly identified exons in human GRM1 express a novel splice variant of metabotropic glutamate 1 receptor.DiRaddo JO et al
229881162012Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling.El Moustaine D et al
239203272013Triple-negative breast cancer and the need for new therapeutic targets.Engebraaten O et al
233034752013Somatic mutations in GRM1 in cancer alter metabotropic glutamate receptor 1 intracellular localization and signaling.Esseltine JL et al
191468762009Metabotropic receptors for glutamate and GABA in pain.Goudet C et al
116724212001Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors.Hermans E et al
218967402011Interdomain movements in metabotropic glutamate receptor activation.Huang S et al
206684512010Diverse somatic mutation patterns and pathway alterations in human cancers.Kan Z et al
163058222006Stimulation of oncogenic metabotropic glutamate receptor 1 in melanoma cells activates ERK1/2 via PKCepsilon.Marín YE et al
173604262007Structures of the extracellular regions of the group II/III metabotropic glutamate receptors.Muto T et al
173323612007Metabotropic glutamate receptor 1 and glutamate signaling in human melanoma.Namkoong J et al
200557062010Metabotropic glutamate receptors: physiology, pharmacology, and disease.Niswender CM et al
83386671993The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins.O'Hara PJ et al
127822432003Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors.Pin JP et al
127043872003Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia.Pollock PM et al
167879232006Coupling of agonist binding to effector domain activation in metabotropic glutamate-like receptors.Rondard P et al
178724292007Comment on "The consensus coding sequences of human breast and colorectal cancers".Rubin AF et al
233327042013Expression, purification, and structural analysis of intracellular C-termini from metabotropic glutamate receptors.Seebahn A et al
184357042008Oncogenic activities of metabotropic glutamate receptor 1 (Grm1) in melanocyte transformation.Shin SS et al
198432462010AKT2 is a downstream target of metabotropic glutamate receptor 1 (Grm1).Shin SS et al
169599742006The consensus coding sequences of human breast and colorectal cancers.Sjöblom T et al
112824172001Glutamate signalling in non-neuronal tissues.Skerry TM et al
216814482012Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer.Speyer CL et al
90767441996Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants.Stephan D et al
226623102012mGlu Receptors and Cancerous Growth.Teh J et al
222733932012Glutamatergic signaling in cellular transformation.Teh JL et al
105814021999Cloning of novel splice variants of mouse mGluR1.Zhu H et al

Other Information

Locus ID:

NCBI: 2911
MIM: 604473
HGNC: 4593
Ensembl: ENSG00000152822


dbSNP: 2911
ClinVar: 2911
TCGA: ENSG00000152822


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Calcium signaling pathwayKEGGko04020
Neuroactive ligand-receptor interactionKEGGko04080
Gap junctionKEGGko04540
Long-term potentiationKEGGko04720
Long-term depressionKEGGko04730
Taste transductionKEGGko04742
Calcium signaling pathwayKEGGhsa04020
Neuroactive ligand-receptor interactionKEGGhsa04080
Gap junctionKEGGhsa04540
Long-term potentiationKEGGhsa04720
Long-term depressionKEGGhsa04730
Taste transductionKEGGhsa04742
Glutamatergic synapseKEGGko04724
Glutamatergic synapseKEGGhsa04724
Retrograde endocannabinoid signalingKEGGhsa04723
Retrograde endocannabinoid signalingKEGGko04723
Estrogen signaling pathwayKEGGhsa04915
Estrogen signaling pathwayKEGGko04915
FoxO signaling pathwayKEGGhsa04068
Neuronal SystemREACTOMER-HSA-112316
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class C/3 (Metabotropic glutamate/pheromone receptors)REACTOMER-HSA-420499
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (q) signalling eventsREACTOMER-HSA-416476
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
Protein-protein interactions at synapsesREACTOMER-HSA-6794362
Interactions of neurexins and neuroligins at synapsesREACTOMER-HSA-6794361

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
246031532014Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator.147
127043872003Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia.108
198745742009Genetical genomic determinants of alcohol consumption in rats and humans.93
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
173323612007Metabotropic glutamate receptor 1 and glutamate signaling in human melanoma.83
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
159450632005Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia.57
248113822014STIM1 controls neuronal Ca²⁺ signaling, mGluR1-dependent synaptic transmission, and cerebellar motor behavior.56
156601242005Evidence for a single heptahelical domain being turned on upon activation of a dimeric GPCR.53
216814482012Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer.50


Jairo Sierra ; Suzie Chen

GRM1 (glutamate receptor, metabotropic 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-08-01

Online version: