Disease relevance of Grin2b

• These results demonstrate that GluRepsilon2-containing NMDA receptors are involved in postoperative pain and that CP-101,606 may be effective in reducing it [1].
• Recent work has shown that a subset of lupus Abs can crossreact with the NR2A and NR2B subunits of the NMDA receptor [2].
• However, pretreatment with CP-101,606 (1 mg/kg), a selective antagonist for the NR2B subunit of the NMDA receptor, significantly attenuated catalepsy and the expression of Fos-IR cells in the forebrain after the administration of haloperidol [3].

Psychiatry related information on Grin2b

• Thalamocortical synaptic plasticity in the mouse is dependent on NMDARs containing the NR2B subunit, which are the dominant form during the "critical period" window for plasticity [4].
• The NR2B KI mice exhibited normal locomotor activity making this ifenprodil-insensitive mouse model a valuable tool to test the specificity of NR2B selective antagonists in vivo [5].
• We conclude that the NR2B-selective conantokins may find utility as neuropharmacological tools for probing NMDAR-related mechanisms of opiate dependence [6].
• Role of NR2B-type NMDA receptors in selective neurodegeneration in Huntington disease [7].
• Together, these results suggest that Fyn can modulate alcohol consumption and prevent behavioural changes during alcohol withdrawal, possibly via phosphorylation of NR2B [8].

High impact information on Grin2b

• Experiments with vesicles containing N-methyl-D-aspartate (NMDA) receptor 2B (NR2B subunit) show that they are transported along microtubules by KIF17, a neuron-specific molecular motor in neuronal dendrites [9].
• Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis [10].
• Transgenic mice exhibited prominent NR2B expression and enhanced NMDA receptor-mediated synaptic responses in two pain-related forebrain areas, the anterior cingulate cortex and insular cortex, but not in the spinal cord [11].
• In particular, it has been suggested that NR2A-containing NMDA receptors are involved in LTP induction, whereas NR2B-containing receptors are involved in LTD induction in the hippocampus [12].
• Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory [12].

Chemical compound and disease context of Grin2b

• Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior [13].

Biological context of Grin2b

• Increased NR2B subunit levels led also to a gradual down-regulation of cerebellar NR2A levels, preceding the development of motor impairment in adult animals [14].
• In a human embryonic kidney (HEK) 293 cell expression system, PTPalpha enhanced fyn-mediated NR2A and NR2B tyrosine phosphorylation by several-fold [15].
• The genes encoding the ionotropic N-methyl-D-aspartate (NMDA) receptor subunits NR1a, NR2B and NR2D were cloned in the multi-copy yeast-Escherichia coli shuttle vectors pMBO1 and pMB02 [16].
• Using reverse-transcription and real-time PCR, we showed that transcript levels of the N-methyl-d-aspartate (NMDA) receptor subunit NR2B are significantly higher in the hippocampus of female ArKO mice compared to wild-type (WT) littermates [17].
• Our data are consistent with the known switch from NR2B to NR2A subunits during the first two postnatal weeks, but suggest a gradual incorporation of the NR2C subunit that modifies Mg(2+) sensitivity and only later influences EPSC kinetics [18].

Anatomical context of Grin2b

• In the hippocampus, the NR2A subunit is believed to be involved in the induction of LTP, whereas the NR2B subunit contributes to the formation of LTD [19].
• Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain [20].
• NR1 and NR2A subunit proteins were detected both in nondifferentiated progenitor cells and in neurons, while the mature form of NR2B subunit protein appeared only at the time of neuronal process elongation [21].
• In order to specify the distinct participation of each of these subunits, we focused on the GluRepsilon2 subunits, which are expressed mainly in the forebrain [22].
• Taking that high levels of GluRepsilon1, GluRepsilon2, and GluRzeta1 subunits are also found in the adult hippocampus and cerebral cortex, it can be assumed that NMDA receptors in developing motoneurons are highly potent and potentially involved in structural and functional development of the brainstem motor system [23].

Associations of Grin2b with chemical compounds

• Ifenprodil, which interacts with polyamine sites of NR2B-containing NMDA receptors, had no effect [24].
• As expected, the inhibition of whole cell currents by the NR2B-specific antagonist, ifenprodil, progressively decreased from 69.5 +/- 2.4% [6 days in vitro (DIV)] to 54.9 +/- 2.6% (8 DIV), before reaching a plateau in the second week (42.5 +/- 2%, 12-19 DIV) [25].
• Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry [20].
• Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice [20].
• The N-methyl-D-aspartate (NMDA)-type glutamate receptor GluRepsilon2 is important for delay and trace eyeblink conditioning in mice [22].

Physical interactions of Grin2b

• In the absence of PSD-93, PSD-95 still interacted with NR2B and nNOS [26].
• We have previously shown that autophosphorylation of CaMKII induces high-affinity binding to the NR2B subunit of the NMDA receptor (Strack, S., and Colbran, R. J. (1998) J. Biol. Chem. 273, 20689-20692) [27].
• These results confirm the observations obtained with other basic molecules and suggest that the behavior induced by poly-l-lysine is mediated through the activation of the NMDA receptor ion-channel complex acting either on the polyamine recognition site or on the NR2B subunit [28].

Regulatory relationships of Grin2b

• Dopamine D(2) receptor blockade was shown to increase both NR2B phosphorylation and the NMDA-induced calcium responses in control cultured striatal neurons but not in Fyn-deficient neurons [29].
• Evidence suggests that, in the CA1 region of the hippocampus, NR2A-containing NMDARs promote LTP whereas NR2B-containing receptors promote LTD [30].
• NR2B inhibits both the Ca(2+)/calmodulin-dependent and autonomous activities of CaMKII by a mechanism that is competitive with autocamtide-2 substrate, non-competitive with syntide-2 substrate, and uncompetitive with respect to ATP [31].
• Differential modulation of Ca2+/calmodulin-dependent protein kinase II activity by regulated interactions with N-methyl-D-aspartate receptor NR2B subunits and alpha-actinin [31].

Other interactions of Grin2b

• Long-term NR2B expression in the cerebellum alters granule cell development and leads to NR2A down-regulation and motor deficits [14].
• GluRepsilon3 subunit mRNAs were not synthesized by NE-7C2 cells and increased numbers of messages from the GluRepsilon2 gene were detected only after neural network formation [32].
• In primary striatal cultures, NT-3 treatment induced an enhancement in NR2A, but not NR2B, protein levels [33].
• Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase [20].
• Immunoblot analyses from behaviorally symptomatic Mecp2-null mice reveal altered expression of N-methyl-d-aspartate receptor subunits NR2A and NR2B [34].

Analytical, diagnostic and therapeutic context of Grin2b

• Semi-quantitative RT-PCR studies on striatal tissue in the oldest age group confirmed the significant decrease in NR2A and also showed a decrease in NR2B [35].
• NR2B protein level was transiently elevated in both trained and stimulated control groups [36].
• Genetic enhancement of inflammatory pain by forebrain NR2B overexpression [11].
• Here, we show that residues 1290-1309 in the cytosolic tail of NR2B are critical for CaMKII binding and identify by site-directed mutagenesis several key residues (Lys(1292), Leu(1298), Arg(1299), Arg(1300), Gln(1301), and Ser(1303)) [27].
• A model is now proposed in which the M2 loop of NR2B is folded in such a way that NR2B(W607) is positioned at the narrow constriction, at a level similar to NR2B(N616) and NR1(N616), with these three residues forming a binding site for Mg2+ [37].

References