Alternative titles; symbols
HGNC Approved Gene Symbol: GRIN3A
Cytogenetic location: 9q31.1 Genomic coordinates (GRCh38): 9:101,569,352-101,738,647 (from NCBI)
N-methyl-D-aspartate (NMDA) receptors belong to the superfamily of glutamate-regulated ion channels and are present in neurons throughout the central nervous system (Andersson et al., 2001).
By screening a human fetal brain cDNA library, Andersson et al. (2001) isolated the GRIN3A cDNA. GRIN3A cDNA contains 3345 bp corresponding to a protein, NR3A, of 1115 amino acids. The human gene showed 72.7% identity to the rat NR3A gene.
Analysis of exon/intron boundaries by Andersson et al. (2001) showed that GRIN3A is encoded by 9 exons.
By sequence analysis, Andersson et al. (2001) mapped the GRIN3A gene to 9q34.
Chatterton et al. (2002) found that NR3B is expressed predominantly in motor neurons, whereas NR3A is more widely distributed. When coexpressed in Xenopus oocytes, NR3A or NR3B coassembles with NR1 (138249) to form excitatory glycine receptors that are unaffected by glutamate or NMDA, and inhibited by D-serine, a coactivator of conventional NMDA receptors. Moreover, Chatterton et al. (2002) found that NR1/NR3A or NR1/NR3B receptors form relatively calcium-impermeable cation channels that are resistant to the open-channel blockers magnesium, MK-801, and memantine, and to competitive antagonists. In cerebrocortical neurons containing NR3 family members, glycine triggers a burst of firing, and membrane patches manifest glycine-responsive single channels that are suppressible by D-serine. By itself, glycine is normally thought of as an inhibitory neurotransmitter. In contrast, these NR1/NR3A or NR1/NR3B NMDA receptors constitute a type of excitatory glycine receptor.
Micu et al. (2006) showed that NMDA glutamate receptors mediate calcium ion accumulation in central myelin in response to chemical ischemia in vitro. Using 2-photon microscopy, they imaged fluorescence of the calcium ion indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the myelin sheath in adult rat optic nerves. The AMPA/kainate receptor antagonist NBQX completely blocked the ischemic calcium ion increase in oligodendroglial cell bodies, but only modestly reduced the calcium ion increase in myelin. In contrast, the calcium ion increase in myelin was abolished by broad-spectrum NMDA receptor antagonists, but not by more selective blockers of NR2A and NR2B subunit-containing receptors. In vitro ischemia causes ultrastructural damage to both axon cylinders and myelin. NMDA receptor antagonism greatly reduced the damage to myelin. NR1, NR2, and NR3 subunits were detected in myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits were present for the formation of functional NMDA receptors. Micu et al. (2006) concluded that their data showed that the mature myelin sheath can respond independently to injurious stimuli. Given that axons are known to release glutamate, the finding that the calcium ion increase is mediated in large part by activation of myelinic NMDA receptors suggested a new mechanism of axomyelinic signaling.
Otsu et al. (2019) discovered that GRIN1 (138249)/GRIN3A receptors are operational in neurons of the mouse adult medial habenula, an epithalamic area controlling aversive physiological states. In the absence of glycinergic neuronal specializations in the medial habenula, glial cells tuned neuronal activity via GRIN1/GRIN3A receptors. Reducing these receptor levels in the medial habenula prevented place-aversion conditioning. Otsu et al. (2019) concluded that their study extended the physiologic and behavioral implications of glycine by demonstrating its control of negatively valued emotional associations via excitatory glycinergic NMDA receptors.
Das et al. (1998) generated mice deficient in NR3A by targeted disruption. Mutant mice had enhanced NMDA responses and increased dendritic spines in early postnatal cerebrocortical neurons, suggesting that NR3A is involved in the development of synaptic elements by modulating NMDAR activity.
Andersson, O., Stenqvist, A., Attersand, A., von Euler, G. Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B. Genomics 78: 178-184, 2001. [PubMed: 11735224] [Full Text: https://doi.org/10.1006/geno.2001.6666]
Chatterton, J. E., Awobuluyi, M., Premkumar, L. S., Takahashi, H., Talantova, M., Shin, Y., Cui, J., Tu, S., Sevarino, K. A., Nakanishi, N., Tong, G., Lipton, S. A., Zhang, D. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415: 793-798, 2002. [PubMed: 11823786] [Full Text: https://doi.org/10.1038/nature715]
Das, S., Sasaki, Y. F., Rothe, T., Premkumar, L. S., Takasu, M., Crandall, J. E., Dikkes, P., Conner, D. A., Rayudu, P. V., Cheung, W., Chen, H.-S. V., Lipton, S. A., Nakanishi, N. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393: 377-381, 1998. [PubMed: 9620802] [Full Text: https://doi.org/10.1038/30748]
Micu, I., Jiang, Q., Coderre, E., Ridsdale, A., Zhang, L., Woulfe, J., Yin, X., Trapp, B. D., McRory, J. E., Rehak, R., Zamponi, G. W., Wang, W., Stys, P. K. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439: 988-992, 2006. [PubMed: 16372019] [Full Text: https://doi.org/10.1038/nature04474]
Otsu, Y., Darcq, E., Pietrajtis, K., Matyas, F., Schwartz, E., Bessaih, T., Abi Gerges, S., Rousseau, C. V., Grand, T., Dieudonne, S., Paoletti, P., Acsady, L., Agulhon, C., Kieffer, B. L., Diana, M. A. Control of aversion by glycine-gated GluN1/GluN3A NMDA receptors in the adult medial habenula. Science 366: 250-254, 2019. [PubMed: 31601771] [Full Text: https://doi.org/10.1126/science.aax1522]