Alternative titles; symbols
HGNC Approved Gene Symbol: GRM3
Cytogenetic location: 7q21.11-q21.12 Genomic coordinates (GRCh38): 7:86,643,909-86,864,879 (from NCBI)
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. Imbalances in glutamatergic function have been implicated in neuronal death following ischemia, in hypoglycemia or anoxia, in epilepsy, and in neurodegenerative disorders. Glutamate actions are mediated by glutamate receptors which fall into 2 distinct classes: ionotropic and metabotropic receptors. Ionotropic glutamate receptors are ligand-gated ion channels whose responses to selective agonists define the N-methyl-D-aspartate (e.g., 138249), alpha-amino-3-hydroxy-5-methyl-isoxasole-4-propionate (e.g., 138248), and kainate (e.g., 138245) subtypes. Metabotropic glutamate receptors, such as GRM3, which are coupled through GTP-binding proteins to second-messenger pathways, can be involved in the stimulation of phospholipase C, the presynaptic inhibition of glutamate release, the closure of cation channels in retinal ON bipolar cells, and the modulation of adenylate cyclase. The 8 distinct metabotropic glutamate receptors that have been identified can be classified into 3 groups according to their sequence similarities, pharmacologic properties, and preferred signal transduction mechanism (Kuramoto et al., 1994).
Bjarnadottir et al. (2005) stated that the deduced 877-amino acid GRM3 protein contains 7 transmembrane domains characteristic of G protein-coupled receptors (GPRs). The N terminus of GRM3 is predicted to function in ligand binding. Bjarnadottir et al. (2005) also identified GRM3 orthologs in mouse and fish. The mouse Grm3 protein contains 879 amino acids.
Bjarnadottir et al. (2005) determined that the GRM3 gene contains 5 exons.
Kuramoto et al. (1994) mapped 6 glutamate receptor genes to rat chromosomes; Scherer et al. (1996) mapped 2 of them, GRM3 and GRM8 (601116), to human 7q. Using a panel of somatic cell hybrids with deletions of various parts of chromosome 7 and fluorescence in situ hybridization, they mapped GRM3 to 7q21.1-q21.2.
Among 304 Swiss individuals tested and genotyped, de Quervain and Papassotiropoulos (2006) found a significant association (p = 0.00008) between short-term episodic memory performance and genetic variations in a 7-gene cluster consisting of the ADCY8 (103070), PRKACG (176893), CAMK2G (602123), GRIN2A (138253), GRIN2B (138252), GRM3, and PRKCA (176960) genes, all of which have well-established molecular and biologic functions in animal memory. Functional MRI studies in an independent set of 32 individuals with similar memory performance showed a correlation between activation in memory-related brain regions, including the hippocampus and parahippocampal gyrus, and genetic variability in the 7-gene cluster. De Quervain and Papassotiropoulos (2006) concluded that these 7 genes encode proteins of the memory formation signaling cascade that are important for human memory function.
Using genomic analysis, immunoelectron microscopy, and 2-photon microscopy of astrocytic calcium ion signaling in vivo, Sun et al. (2013) found that astrocyte expression of mGluR5 (604102) is developmentally regulated and is undetectable after postnatal week 3 in the mouse. In contrast, mGluR3, whose activation inhibits adenylate cyclase but not calcium signaling, was expressed in astrocytes at all developmental stages. Sun et al. (2013) concluded that neuroglial signaling in the adult brain may therefore occur in a manner fundamentally distinct from that exhibited during development.
Using single-strand conformation analysis, Marti et al. (2002) screened the complete coding sequence of the GRM3 gene and adjacent splice sites in a sample of 46 bipolar affective and 46 schizophrenic patients. They detected 3 sequence variants but could not establish a major role for any of them in predisposing to schizophrenia and/or bipolar affective disorder in the German population.
Prickett et al. (2011) used exon capture and massively parallel sequencing methods to analyze the mutational status of 734 G protein-coupled receptors in melanoma. This investigation revealed that one family member, GRM3, was frequently mutated and that 1 of its mutations was recurrent. Biochemical analysis of GRM3 alterations revealed that mutant GRM3 selectively regulated the phosphorylation of MAPK/ERK kinase (MEK; see 176872), leading to increased anchorage-independent growth and migration. Melanoma cells expressing mutant GRM3 had reduced cell growth and cellular migration after short hairpin RNA-mediated knockdown of GRM3 or treatment with a selective MEK inhibitor. Prickett et al. (2011) found that 16.3% of melanomas were affected with GRM3 mutations. Prickett et al. (2011) found the GRM3 glu870-to-lys mutation in 4 different individuals with melanoma.
Bjarnadottir, T. K., Fredriksson, R., Schioth, H. B. The gene repertoire and the common evolutionary history of glutamate, pheromone (V2R), taste(1) and other related G protein-coupled receptors. Gene 362: 70-84, 2005. [PubMed: 16229975] [Full Text: https://doi.org/10.1016/j.gene.2005.07.029]
de Quervain, D. J.-F., Papassotiropoulos, A. Identification of a genetic cluster influencing memory performance and hippocampal activity in humans. Proc. Nat. Acad. Sci. 103: 4270-4274, 2006. [PubMed: 16537520] [Full Text: https://doi.org/10.1073/pnas.0510212103]
Kuramoto, T., Maihara, T., Masu, M., Nakanishi, S., Serikawa, T. Gene mapping of NMDA receptors and metabotropic glutamate receptors in the rat (Rattus norvegicus). Genomics 19: 358-361, 1994. [PubMed: 8188265] [Full Text: https://doi.org/10.1006/geno.1994.1069]
Marti, S. B., Cichon, S., Propping, P., Nothen, M. Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population. Am. J. Med. Genet. 114B: 46-50, 2002. [PubMed: 11840505] [Full Text: https://doi.org/10.1002/ajmg.1624]
Prickett, T. D., Wei, X., Cardenas-Navia, I., Teer, J. K., Lin, J. C., Walia, V., Gartner, J., Jiang, J., Cherukuri, P. F., Molinolo, A., Davies, M. A., Gershenwald, J. E., Stemke-Hale, K., Rosenberg, S. A., Margulies, E. H., Samuels, Y. Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. Nature Genet. 43: 1119-1126, 2011. [PubMed: 21946352] [Full Text: https://doi.org/10.1038/ng.950]
Scherer, S. W., Duvoisin, R. M., Kuhn, R., Heng, H. H. Q., Belloni, E., Tsui, L.-C. Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q. Genomics 31: 230-233, 1996. [PubMed: 8824806] [Full Text: https://doi.org/10.1006/geno.1996.0036]
Sun, W., McConnell, E., Pare, J.-F., Xu, Q., Chen, M., Peng, W., Lovatt, D., Han, X., Smith, Y., Nedergaard, M. Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science 339: 197-200, 2013. [PubMed: 23307741] [Full Text: https://doi.org/10.1126/science.1226740]