Alternative titles; symbols
HGNC Approved Gene Symbol: GRIN2C
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38): 17:74,842,023-74,861,532 (from NCBI)
The NMDA receptors are 1 class of ionotropic glutamate receptors (see GRIN2D; 602717). By screening a human hippocampal cDNA library with a rat Nr2a (GRIN2A; 138253) cDNA, Lin et al. (1996) isolated cDNAs encoding GRIN2C, called NR2C by them. Northern blot analysis showed that the 4.4-kb GRIN2C mRNA was widely expressed in the brain, with the highest level of expression in the cerebellum; this transcript was also found in several other tissues. An additional, slightly larger, transcript was detected in the cerebellum. The sequence of the deduced 1,233-amino acid protein is 88% identical to those of rat and mouse Nr2c. Hydropathy analysis of GRIN2C predicted a large N terminus, 4 hydrophobic regions, and a large C terminus.
Takano et al. (1993) used fluorescence in situ hybridization to map the gene for the epsilon-3 subunit of the human NMDA receptor channel to 17q25. Kalsi et al. (1998) confirmed this localization by PCR of a somatic cell hybrid panel.
Hardingham et al. (2002) reported that synaptic and extrasynaptic NMDA receptors have opposite effects on CREB (123810) function, gene regulation, and neuronal survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF; 113505) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have antiapoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death.
Ozaki et al. (1997) found that a neuregulin-beta isoform (NRG1; 142445) increased expression of the NR2C subunit of the NMDA receptor in cultured mouse cerebellar slices and that this upregulation also required synaptic activity by NMDA receptors. The findings suggested that neuregulins regulate the composition of neurotransmitter receptors in maturing synapses in the brain.
Gielen et al. (2009) showed that the subunit-specific gating of NMDA receptors (NMDARs) is controlled by the region formed by the NR2 N-terminal domain (NTD), an extracellular clamshell-like domain that binds allosteric inhibitors, and the short linker connecting the NTD to the agonist-binding domain (ABD). The subtype specificity of NMDAR maximum open probability (P-O) largely reflects differences in the spontaneous (ligand-independent) equilibrium between open-cleft and closed-cleft conformations of the NR2 NTD. This NTD-driven gating control also affects pharmacologic properties by setting the sensitivity to the endogenous inhibitors zinc and protons. Gielen et al. (2009) concluded that their results provided a proof of concept for a drug-based bidirectional control of NMDAR activity by using molecules acting either as NR2 NTD 'closers' or 'openers' promoting receptor inhibition or potentiation, respectively.
Kadotani et al. (1996) showed that targeted disruption of the mouse Nmdar2c gene produced homozygous -/- mice with no obvious deficiency. By gene targeting, Sprengel et al. (1998) generated mutant mice expressing the Nmdar2c gene without the large intracellular C-terminal domain. These mice were viable but exhibited deficits in motor coordination. The authors concluded that the observed phenotypes appear to reflect defective intracellular signaling.
Gielen, M., Siegler Retchless, B., Mony, L., Johnson, J. W., Paoletti, P. Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature 459: 703-707, 2009. [PubMed: 19404260] [Full Text: https://doi.org/10.1038/nature07993]
Hardingham, G. E., Fukunaga, Y., Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nature Neurosci. 5: 405-414, 2002. [PubMed: 11953750] [Full Text: https://doi.org/10.1038/nn835]
Kadotani, H., Hirano, T., Masugi, M., Nakamura, K., Nakao, K., Katsuki, M., Nakanishi, S. Motor discoordination results from combined gene disruption of the NMDA receptor NR2A and NR2C subunits, but not from single disruption of the NR2A or NR2C subunit. J. Neurosci. 16: 7859-7867, 1996. [PubMed: 8987814] [Full Text: https://doi.org/10.1523/JNEUROSCI.16-24-07859.1996]
Kalsi, G., Whiting, P., Le Bourdelles, B., Callen, D., Barnard, E. A., Gurling, H. Localization of the human NMDAR2D receptor subunit gene (GRIN2D) to 19q13.1-qter, the NMDAR2A subunit gene to 16p13.2 (GRIN2A), and the NMDAR2C subunit gene (GRIN2C) to 17q24-q25 using somatic cell hybrid and radiation hybrid mapping panels. Genomics 47: 423-425, 1998. [PubMed: 9480759] [Full Text: https://doi.org/10.1006/geno.1997.5132]
Lin, Y. J., Bovetto, S., Carver, J. M., Giordano, T. Cloning of the cDNA for the human NMDA receptor NR2C subunit and its expression in the central nervous system and periphery. Molec. Brain Res. 43: 57-64, 1996. [PubMed: 9037519] [Full Text: https://doi.org/10.1016/s0169-328x(96)00146-5]
Ozaki, M., Sasner, M., Yano, R., Lu, H. S., Buonanno, A. Neuregulin-beta induces expression of an NMDA-receptor subunit. Nature 390: 691-694, 1997. [PubMed: 9414162] [Full Text: https://doi.org/10.1038/37795]
Sprengel, R., Suchanek, B., Amico, C., Brusa, R., Burnashev, N., Rozov, A., Hvalby, O., Jensen, V., Paulsen, O., Andersen, P., Kim, J. J., Thompson, R. F., Sun, W., Webster, L. C., Grant, S. G. N., Eilers, J., Konnerth, A., Li, J., McNamara, J. O., Seeburg, P. H. Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92: 279-289, 1998. [PubMed: 9458051] [Full Text: https://doi.org/10.1016/s0092-8674(00)80921-6]
Takano, H., Onodera, O., Tanaka, H., Mori, H., Sakimura, K., Hori, T., Kobayashi, H., Mishina, M., Tsuji, S. Chromosomal localization of the epsilon-1, epsilon-3, and zeta-1 subunit genes of the human NMDA receptor channel. Biochem. Biophys. Res. Commun. 197: 922-926, 1993. [PubMed: 8267632] [Full Text: https://doi.org/10.1006/bbrc.1993.2567]