9pzs

Structural highlights

Function

NMDE2_MOUSE Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+) (PubMed:26912815). Participates in synaptic plasticity for learning and memory formation by contributing to the long-term depression (LTD) of hippocampus membrane currents (PubMed:8789948). Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (Probable) (PubMed:1377365, PubMed:20141836, PubMed:7790891). NMDARs mediate simultaneously the potasium efflux and the influx of calcium and sodium (By similarity). Each GluN2 subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, Ca2(+) permeability, and binding to allosteric modulators (By similarity). In concert with DAPK1 at extrasynaptic sites, acts as a central mediator for stroke damage (PubMed:20141836). Its phosphorylation at Ser-1303 by DAPK1 enhances synaptic NMDA receptor channel activity inducing injurious Ca2+ influx through them, resulting in an irreversible neuronal death (PubMed:20141836).[UniProtKB:P35438][UniProtKB:Q13224]^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ Kutsuwada T, Kashiwabuchi N, Mori H, Sakimura K, Kushiya E, Araki K, Meguro H, Masaki H, Kumanishi T, Arakawa M, et al.. Molecular diversity of the NMDA receptor channel. Nature. 1992 Jul 2;358(6381):36-41. PMID:1377365 doi:10.1038/358036a0
2. ↑ Tu W, Xu X, Peng L, Zhong X, Zhang W, Soundarapandian MM, Balel C, Wang M, Jia N, Zhang W, Lew F, Chan SL, Chen Y, Lu Y. DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell. 2010 Jan 22;140(2):222-34. PMID:20141836 doi:10.1016/j.cell.2009.12.055
3. ↑ Stroebel D, Buhl DL, Knafels JD, Chanda PK, Green M, Sciabola S, Mony L, Paoletti P, Pandit J. A novel binding mode reveals two distinct classes of NMDA receptor GluN2B-selective antagonists. Mol Pharmacol. 2016 Feb 24. pii: mol.115.103036. PMID:26912815 doi:http://dx.doi.org/10.1124/mol.115.103036
4. ↑ Matsui T, Sekiguchi M, Hashimoto A, Tomita U, Nishikawa T, Wada K. Functional comparison of D-serine and glycine in rodents: the effect on cloned NMDA receptors and the extracellular concentration. J Neurochem. 1995 Jul;65(1):454-8. PMID:7790891 doi:10.1046/j.1471-4159.1995.65010454.x
5. ↑ Kutsuwada T, Sakimura K, Manabe T, Takayama C, Katakura N, Kushiya E, Natsume R, Watanabe M, Inoue Y, Yagi T, Aizawa S, Arakawa M, Takahashi T, Nakamura Y, Mori H, Mishina M. Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice. Neuron. 1996 Feb;16(2):333-44. PMID:8789948 doi:10.1016/s0896-6273(00)80051-3
6. ↑ Stroebel D, Buhl DL, Knafels JD, Chanda PK, Green M, Sciabola S, Mony L, Paoletti P, Pandit J. A novel binding mode reveals two distinct classes of NMDA receptor GluN2B-selective antagonists. Mol Pharmacol. 2016 Feb 24. pii: mol.115.103036. PMID:26912815 doi:http://dx.doi.org/10.1124/mol.115.103036