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Grin2b  -  glutamate receptor, ionotropic, N-methyl D...

Rattus norvegicus

Synonyms: GluN2B, Glutamate receptor ionotropic, NMDA 2B, N-methyl D-aspartate receptor subtype 2B, NMDAR2B, NR2B
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Disease relevance of Grin2b

  • Following ischemia, NR1, NR2A and NR2B levels were elevated in PSDs and reduced in lipid rafts [1].
  • The long-lasting shift towards increased NR2B and decreased NR2D messenger RNA expression after kindling suggests that N-methyl-D-aspartate receptor NR2 composition may be an important factor in the maintenance of pathological plasticity following generalized seizures [2].
  • PC12 cells co-infected with recombinant adenoviruses bearing NR1 and NR2B cDNAs expressed conventional NMDA receptors that were permeable to Ca2+ and sensitive to Mg2+, whereas those with viruses bearing NR1(N598R) and NR2B cDNAs expressed Ca2+-impermeable and Mg2+-insensitive receptors [3].
  • Hindpaw inflammation induces tyrosine phosphorylation (tyr-P) of the NMDA receptor (NMDAR) 2B (NR2B) subunit in the rat spinal dorsal horn that is closely related to the initiation and development of hyperalgesia [4].
  • A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia [5].

Psychiatry related information on Grin2b


High impact information on Grin2b

  • Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking [10].
  • In mature neurons, NR2B is coupled to inhibition rather than activation of the Ras-ERK pathway, which drives surface delivery of GluR1 [10].
  • Preferential coupling of NR2B to SynGAP could explain the subtype-specific function of NR2B-NMDARs in inhibition of Ras-ERK, removal of synaptic AMPARs, and weakening of synaptic transmission [10].
  • This study identifies a dynamic regulation of synaptic NR2B-containing NMDARs through PDZ protein-mediated stabilization and AP-2-mediated internalization that is modulated by phosphorylation by Fyn kinase [11].
  • The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2 [11].

Chemical compound and disease context of Grin2b


Biological context of Grin2b

  • The spectrin-NR2B interactions are antagonized by Ca2+ and fyn-mediated NR2B phosphorylation, but not by Ca2+/calmodulin (CaM) or by Ca2+/CaM-dependent protein kinase II-mediated NR2B phosphorylation [15].
  • The competitive NMDA antagonist R-(-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (D-CPP), which has higher affinity to NR2A than to NR2B subunits and lowest affinity at NR2D subunits, significantly slowed down the decay rate of the afterburst EPSC while leaving the kinetics of the control current unaffected [16].
  • The blockage of the gene expression of NR2B is therefore specific and the present results may provide important implications in applications of antisense in research and in clinical therapy of neurological diseases [17].
  • 3. Memantine, an open-channel blocker, and ifenprodil, a preferential non-competitive NR1/NR2B receptor antagonist diminished the NMDA effect with an IC50 value of 0.17 and 1 microM, respectively [18].
  • NR1, NR2A, and NR2B mRNA levels were measured by RNase protection assay in young (3-4 month), middle-aged (12-13 month), and aged (24-25 month) Sprague-Dawley rats in different phases of the estrous cycle in cycling animals and in acyclic subjects [19].

Anatomical context of Grin2b

  • Finally, in rat synaptosomes, both spectrin and NR2B are loosened from membranes upon addition of physiological concentrations of calcium ions [15].
  • This pattern was identical to that observed for cerebellar (NR2C-containing) versus forebrain (NR2A- and NR2B-containing) NMDA receptors [20].
  • NMDA receptors in the lateral thalamus (with a high density of NR2A subunit mRNA) displayed higher affinity for antagonists and a lower affinity for agonists than did NMDA receptors of the medial striatum (a region rich in NR2B mRNA) [20].
  • By immunostaining of rat heart tissue slices and acutely dissociated cardiac myocytes, the NR2B antigen was localized at the sarcomeric Z-bands [21].
  • Differences in antibody recognition indicate that the cardiac NR2B polypeptide carries a structurally altered C terminus as compared with the NR2B variant prevalent in central nervous system [21].

Associations of Grin2b with chemical compounds

  • Each cysteine residue in the NMDAR1 (NR1) subunit and each conserved NMDAR2 (NR2) cysteine residue in a prototypical subunit (NR2B) was tested for its role in redox modulation [22].
  • We identify a phosphorylation site, serine 1244 (Ser(1244)), near the extreme COOH terminus of NR2C, which is phosphorylated by both cAMP-dependent protein kinase and protein kinase C. This residue is located adjacent to the consensus PDZ ligand, a region that regulates protein-protein interactions and receptor trafficking in NR2A and NR2B [23].
  • However, most of the functional properties of NMDA-Rs in these neurones, including the strong inhibition by ifenprodil and Mg2+, the high fractional Ca2+ current, and the time course of the synaptic currents, are more consistent with those known for NR2B than for the other NR2 subunits [24].
  • The aim of this study was to test whether this effect could be mediated by direct tyrosine phosphorylation of the NR2A or NR2B subunits of the receptor [25].
  • As the density of active synapses increases, the confluence of released glutamate makes EPSC decay much longer by activating more extrasynaptic NR2B- and NR2D-subunit-containing receptors [16].
  • We demonstrate that the neuroprotective effects of PDGF-BB are occluded by the NR2B antagonist, Ro25-6981, and that PDGF-BB promotes NMDA signaling to CREB and ERK1/2 [26].

Physical interactions of Grin2b

  • In contrast, the NR2A subunit localizes to the synapse in the absence of PDZ binding and is not altered by mutations in its motif corresponding to YEKL of NR2B [11].
  • All three PDZ domains in SAP102 bind the cytoplasmic tail of NR2B in vitro [27].
  • Coincidence in dendritic clustering and synaptic targeting of homer proteins and NMDA receptor complex proteins NR2B and PSD95 during development of cultured hippocampal neurons [28].
  • PI3-kinase p85 was co-precipitated with NR2B after transient global ischemia [29].
  • The binding site of the active components in the extract overlapped with the nNOS/NR2B-binding pocket of PDZ2 of PSD-95 [30].

Co-localisations of Grin2b

  • However, after ischemia-induced neuronal death in these regions, double immunohistochemical labeling revealed that NR2B subunits colocalized with the astrocyte marker glial fibrillary acid protein and with NR1 subunits that are required for functional NMDA receptors [31].

Regulatory relationships of Grin2b


Other interactions of Grin2b

  • In 5 mM KCl, a similar, rapid increase in NR2A was observed, but disappearance of NR2B occurred over a longer time course [34].
  • At a moderate level were GluR6, NR2B, and NR2D [35].
  • We further found that in hippocampal slices, both RACK1 and NR2B associated with another WD40 protein, the beta-subunit of G protein (Gbeta), previously shown to heterodimerize with RACK1 in vitro (Dell, E. J., Connor, J., Chen, S., Stebbins, E. G., Skiba, N. P., Mochly-Rosen, D., and Hamm, H. E. (2002) J. Biol. Chem. 277, 49888-49895) [36].
  • In a dorsal horn slice preparation, the group I (dihydroxyphenylglycine), but not group II [(2R,4R)-4-aminopyrrolidine-2,3-dicarboxylate] and III [L-AP 4 (L-(+)-2-amino-4-phosphonobutyric acid)], mGluR agonists, an IP3 receptor (D-IP3) agonist, and a PKC (PMA) activator, induces NR2B tyr-P similar to that seen in vivo after inflammation [4].
  • On the other hand, the NR2B antisense ODN had no effect on either NR2B protein or on Bax [37].

Analytical, diagnostic and therapeutic context of Grin2b


  1. Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and post-synaptic densities following transient global ischemia in the rat brain. Besshoh, S., Bawa, D., Teves, L., Wallace, M.C., Gurd, J.W. J. Neurochem. (2005) [Pubmed]
  2. Amygdala kindling alters N-methyl-D-aspartate receptor subunit messenger RNA expression in the rat supraoptic nucleus. Al-Ghoul, W.M., Meeker, R.B., Greenwood, R.S. Neuroscience (1997) [Pubmed]
  3. Expression of recombinant NMDA receptors in hippocampal neurons by adenoviral-mediated gene transfer. Yamada, N., Sudo, M., Okado, H., Iino, M., Tsuzuki, K., Miwa, A., Ozawa, S. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  4. Group I metabotropic glutamate receptor NMDA receptor coupling and signaling cascade mediate spinal dorsal horn NMDA receptor 2B tyrosine phosphorylation associated with inflammatory hyperalgesia. Guo, W., Wei, F., Zou, S., Robbins, M.T., Sugiyo, S., Ikeda, T., Tu, J.C., Worley, P.F., Dubner, R., Ren, K. J. Neurosci. (2004) [Pubmed]
  5. A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia. Gardoni, F., Picconi, B., Ghiglieri, V., Polli, F., Bagetta, V., Bernardi, G., Cattabeni, F., Di Luca, M., Calabresi, P. J. Neurosci. (2006) [Pubmed]
  6. The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats. Ma, Y.Y., Guo, C.Y., Yu, P., Lee, D.Y., Han, J.S., Cui, C.L. Exp. Neurol. (2006) [Pubmed]
  7. The NR2B-selective N-methyl-D-aspartate receptor antagonist Ro 25-6981 [(+/-)-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propanol] potentiates the effect of nicotine on locomotor activity and dopamine release in the nucleus accumbens. Kosowski, A.R., Liljequist, S. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  8. Differential effects of electroconvulsive shock on the glutamate receptor mRNAs for NR2A, NR2B and mGluR5b. Watkins, C.J., Pei, Q., Newberry, N.R. Brain Res. Mol. Brain Res. (1998) [Pubmed]
  9. Nicotine exposure during a postnatal critical period alters NR2A and NR2B mRNA expression in rat auditory forebrain. Hsieh, C.Y., Leslie, F.M., Metherate, R. Brain Res. Dev. Brain Res. (2002) [Pubmed]
  10. Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Kim, M.J., Dunah, A.W., Wang, Y.T., Sheng, M. Neuron (2005) [Pubmed]
  11. The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Prybylowski, K., Chang, K., Sans, N., Kan, L., Vicini, S., Wenthold, R.J. Neuron (2005) [Pubmed]
  12. Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-D-aspartate receptor redistribution. Abulrob, A., Tauskela, J.S., Mealing, G., Brunette, E., Faid, K., Stanimirovic, D. J. Neurochem. (2005) [Pubmed]
  13. Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist. Taniguchi, K., Shinjo, K., Mizutani, M., Shimada, K., Ishikawa, T., Menniti, F.S., Nagahisa, A. Br. J. Pharmacol. (1997) [Pubmed]
  14. Epilepsy, neurodegeneration, and extracellular glutamate in the hippocampus of awake and anesthetized rats treated with okadaic acid. Ramírez-Munguía, N., Vera, G., Tapia, R. Neurochem. Res. (2003) [Pubmed]
  15. Brain spectrin binding to the NMDA receptor is regulated by phosphorylation, calcium and calmodulin. Wechsler, A., Teichberg, V.I. EMBO J. (1998) [Pubmed]
  16. Extrasynaptic NR2B and NR2D subunits of NMDA receptors shape 'superslow' afterburst EPSC in rat hippocampus. Lozovaya, N.A., Grebenyuk, S.E., Tsintsadze, T.S.h., Feng, B., Monaghan, D.T., Krishtal, O.A. J. Physiol. (Lond.) (2004) [Pubmed]
  17. Modulation of the gene expression of N-methyl-D-aspartate receptor NR2B subunit in the rat neostriatum by a single dose of specific antisense oligodeoxynucleotide. Sze, S.C., Wong, C.K., Yung, K.K. Neurochem. Int. (2001) [Pubmed]
  18. NMDA receptor characterization and subunit expression in rat cultured mesencephalic neurones. Allgaier, C., Scheibler, P., Müller, D., Feuerstein, T.J., Illes, P. Br. J. Pharmacol. (1999) [Pubmed]
  19. N-methyl-D-aspartate receptor mRNA levels change during reproductive senescence in the hippocampus of female rats. Adams, M.M., Morrison, J.H., Gore, A.C. Exp. Neurol. (2001) [Pubmed]
  20. The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition. Buller, A.L., Larson, H.C., Schneider, B.E., Beaton, J.A., Morrisett, R.A., Monaghan, D.T. J. Neurosci. (1994) [Pubmed]
  21. Formation of molecular complexes by N-methyl-D-aspartate receptor subunit NR2B and ryanodine receptor 2 in neonatal rat myocard. Seeber, S., Humeny, A., Herkert, M., Rau, T., Eschenhagen, T., Becker, C.M. J. Biol. Chem. (2004) [Pubmed]
  22. Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor. Sullivan, J.M., Traynelis, S.F., Chen, H.S., Escobar, W., Heinemann, S.F., Lipton, S.A. Neuron (1994) [Pubmed]
  23. Regulation of NR1/NR2C N-methyl-D-aspartate (NMDA) receptors by phosphorylation. Chen, B.S., Braud, S., Badger, J.D., Isaac, J.T., Roche, K.W. J. Biol. Chem. (2006) [Pubmed]
  24. Molecular determinants of NMDA receptor function in GABAergic neurones of rat forebrain. Plant, T., Schirra, C., Garaschuk, O., Rossier, J., Konnerth, A. J. Physiol. (Lond.) (1997) [Pubmed]
  25. Protein kinase C activation induces tyrosine phosphorylation of the NR2A and NR2B subunits of the NMDA receptor. Grosshans, D.R., Browning, M.D. J. Neurochem. (2001) [Pubmed]
  26. Platelet-derived growth factor selectively inhibits NR2B-containing N-methyl-D-aspartate receptors in CA1 hippocampal neurons. Beazely, M.A., Lim, A., Li, H., Trepanier, C., Chen, X., Sidhu, B., Macdonald, J.F. J. Biol. Chem. (2009) [Pubmed]
  27. SAP102, a novel postsynaptic protein that interacts with NMDA receptor complexes in vivo. Müller, B.M., Kistner, U., Kindler, S., Chung, W.J., Kuhlendahl, S., Fenster, S.D., Lau, L.F., Veh, R.W., Huganir, R.L., Gundelfinger, E.D., Garner, C.C. Neuron (1996) [Pubmed]
  28. Coincidence in dendritic clustering and synaptic targeting of homer proteins and NMDA receptor complex proteins NR2B and PSD95 during development of cultured hippocampal neurons. Shiraishi, Y., Mizutani, A., Mikoshiba, K., Furuichi, T. Mol. Cell. Neurosci. (2003) [Pubmed]
  29. Transient ischemia enhances tyrosine phosphorylation and binding of the NMDA receptor to the Src homology 2 domain of phosphatidylinositol 3-kinase in the rat hippocampus. Takagi, N., Sasakawa, K., Besshoh, S., Miyake-Takagi, K., Takeo, S. J. Neurochem. (2003) [Pubmed]
  30. Flavonoids from Radix Scutellariae as potential stroke therapeutic agents by targeting the second postsynaptic density 95 (PSD-95)/disc large/zonula occludens-1 (PDZ) domain of PSD-95. Tang, W., Sun, X., Fang, J.S., Zhang, M., Sucher, N.J. Phytomedicine (2004) [Pubmed]
  31. Functional NMDA receptor subtype 2B is expressed in astrocytes after ischemia in vivo and anoxia in vitro. Krebs, C., Fernandes, H.B., Sheldon, C., Raymond, L.A., Baimbridge, K.G. J. Neurosci. (2003) [Pubmed]
  32. Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. Fischer, G., Mutel, V., Trube, G., Malherbe, P., Kew, J.N., Mohacsi, E., Heitz, M.P., Kemp, J.A. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  33. Characterization of NMDA receptor subunit-specific antibodies: distribution of NR2A and NR2B receptor subunits in rat brain and ontogenic profile in the cerebellum. Wang, Y.H., Bosy, T.Z., Yasuda, R.P., Grayson, D.R., Vicini, S., Pizzorusso, T., Wolfe, B.B. J. Neurochem. (1995) [Pubmed]
  34. Neuronal activity differentially regulates NMDA receptor subunit expression in cerebellar granule cells. Vallano, M.L., Lambolez, B., Audinat, E., Rossier, J. J. Neurosci. (1996) [Pubmed]
  35. Expression of AMPA, kainate, and NMDA receptor subunits in cochlear and vestibular ganglia. Niedzielski, A.S., Wenthold, R.J. J. Neurosci. (1995) [Pubmed]
  36. Spatial and temporal regulation of RACK1 function and N-methyl-D-aspartate receptor activity through WD40 motif-mediated dimerization. Thornton, C., Tang, K.C., Phamluong, K., Luong, K., Vagts, A., Nikanjam, D., Yaka, R., Ron, D. J. Biol. Chem. (2004) [Pubmed]
  37. The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture. Wang, C., Fridley, J., Johnson, K.M. Biochem. Pharmacol. (2005) [Pubmed]
  38. The NMDA receptor subunits NR2A and NR2B show histological and ultrastructural localization patterns similar to those of NR1. Petralia, R.S., Wang, Y.X., Wenthold, R.J. J. Neurosci. (1994) [Pubmed]
  39. Estrogen-like activity of tamoxifen and raloxifene on NMDA receptor binding and expression of its subunits in rat brain. Cyr, M., Thibault, C., Morissette, M., Landry, M., Di Paolo, T. Neuropsychopharmacology (2001) [Pubmed]
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