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

• Experimental results showed that (1) an augmented expression of NR2B subunit was revealed by Western blotting in the nucleus accumbens (NAc) and the hippocampus in rats with CPP induced by morphine, but not by natural rewards such as food, novel environment and social interaction [6].
• Taking together, these findings suggested that NR2B containing NMDA receptor may be more involved with morphine reward rather than natural rewards, and that antagonism of NR2B may have a potential for the treatment of morphine abuse [6].
• 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 [7].
• Differential effects of electroconvulsive shock on the glutamate receptor mRNAs for NR2A, NR2B and mGluR5b [8].
• Nicotine exposure during a postnatal critical period alters NR2A and NR2B mRNA expression in rat auditory forebrain [9].

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

• (2) Ifenprodil, an antagonist highly selective for NR2B subunit of the NMDA receptor, produced a dose-dependent reduction in CPP induced by morphine and novel environment, but not that by food consumption and social interaction [6].
• Cholesterol repletion counteracted the ability of methylated beta-CD to protect against NMDA toxicity, and reversed NR2B, PSD-95 and nNOS localization to Triton X-100 insoluble membrane fraction [12].
• 1. The analgesic activity of CP-101,606, an NR2B subunit-selective N-methyl-D-aspartate (NMDA) receptor antagonist, was examined in carrageenan-induced hyperalgesia, capsaicin- and 4beta-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive tests in the rat [13].
• We have previously shown that the intrahippocampal microinjection of okadaic acid (OKA), a potent inhibitor of serine/threonine protein phosphatases, induces epileptic seizures, neuronal death, and the hyperphosphorylation of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor [14].

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

• An increase in tyrosine phosphorylation of both NR2A (76 +/- 11% above control) and NR2B (41 +/- 11%) was observed [25].
• Thus, inflammation and mGluR-induced NR2B tyr-P share similar mechanisms [4].
• NMDA receptor subtypes expressed in Xenopus oocytes were blocked with IC50 values of 0.009 microM and 52 microM for the subunit combinations NR1C & NR2B and NR1C & NR2A, respectively, which indicated a >5000-fold selectivity [32].
• The NR2B subunit was found to be expressed at its highest levels in the olfactory tubercle, hippocampus, olfactory bulb, and cerebral cortex [33].

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

• In Western blots of rat brain, the antibody labeled a single band that comigrated with NR2A and NR2B [38].
• Using immunoprecipitation of detergent-solubilized NR2B protein and subsequent analysis employing matrix-assisted laser desorption/ionization time of flight mass spectrometry, ryanodine receptor 2 was identified as a molecular interaction partner of the cardiac NR2B polypeptide [21].
• [3H]Ro 25-6981 (an NMDA antagonist selective for NR1/NR2B assembly) specific binding and mRNA levels of NMDA receptor subunits 1 and 2B decreased in CA1 after ovariectomy [39].
• The mRNA level of NR2B in the ANR2B-injected neostriatum was found to be decreased (-20.4%) by reverse transcriptase polymerase chain reaction (RT-PCR) [17].
• After two days of injection, NR2B immunoreactivity was found to decrease in the ANR2B-treated neostriatum by immunofluorescence (-35.1%) [17].

References