Disease relevance of Grin2a

• Following ischemia, tyrosine phosphorylation of NR2A and NR2B and activated Src-family kinases (SFKs) and Pyk2 were increased in post-synaptic densities (PSDs) [1].
• Association between Fyn and NR2A increased immediately after brain ischemia and the increase was maintained for at least 24 h during followed reperfusion, up to about 1.7-1.8-fold relative to sham-groups [2].
• Increased NR1-NR2A/B coassembly as a mechanism for rat chronic hippocampal epilepsy [3].
• To test this hypothesis, adult rats were subjected to a lateral fluid percussion brain injury and the NR1, NR2A and NR2B subunits measured within different regions [4].
• Repetitive febrile seizures in rat pups cause long-lasting deficits in synaptic plasticity and NR2A tyrosine phosphorylation [5].

Psychiatry related information on Grin2a

• Here we examine whether this developmental regulation of NR2A expression is related to the duration of critical periods and whether it is influenced by experience [6].
• Differential effects of electroconvulsive shock on the glutamate receptor mRNAs for NR2A, NR2B and mGluR5b [7].

High impact information on Grin2a

• Two regions in the D1 receptor carboxyl tail can directly and selectively couple to NMDA glutamate receptor subunits NR1-1a and NR2A [8].
• By co-immunoprecipitation with subunit-specific antibodies, we present here direct evidence that NMDA receptors exist in rat neocortex as heteromeric complexes of considerable heterogeneity, some containing both NR2A and NR2B subunits [9].
• Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking [10].
• AMPA receptor-dependent clustering of synaptic NMDA receptors is mediated by Stargazin and NR2A/B in spinal neurons and hippocampal interneurons [11].
• The apparent affinity for Zn2+ of the heteromeric NMDA receptors is determined by the subtype of NR2 subunit expressed, with NR2A-containing receptors being the most sensitive (IC50, approximately 20 nM) and NR2C-containing receptors being the least sensitive (IC50, approximately 30 microM) [12].

Chemical compound and disease context of Grin2a

• To investigate whether the above processes are involved in brain ischemia-induced enhancement of NMDA receptors function, we examined the effects of transient (15 min) brain ischemia followed by reperfusion on interactions involving Fyn, NR2A and PSD95 in rat hippocampus by co-immunoprecipitation [2].
• The following results were observed: (1) the increase in tyrosine phosphorylation of NR2A induced by I/R was suppressed by genistein, an inhibitor of PTK, but was further enhanced by sodium orthovanadate, an inhibitor of PTP, which were administered to the SD rats 20 min before ischemia [13].
• Reactive astrocytes exhibited kainate, GluR5-7, and N-methyl-D-aspartate (NMDA), NR2A/B, receptor subunits, both of which were maximally expressed approximately 4 weeks after ischemia [14].
• Nicotine exposure during a postnatal critical period alters NR2A and NR2B mRNA expression in rat auditory forebrain [15].
• CONCLUSION: ONO-1078 possesses a neuroprotective effect on global cerebral ischemia in rats, and its mechanism may be partly related to the inhibition of the upregulation of NR2A and VCAM-1 in different regions of the brain [16].

Biological context of Grin2a

• The distribution of NR2A mRNA was very similar to that of "antagonist-preferring" NMDA receptors [defined by high-affinity 3H-2-carboxypiperazine-4-yl-propyl-1-phosphonic (3H-CPP) binding sites; correlation coefficient = 0.88] [17].
• In situ granule-cell maturation is associated with downregulation of NR2B and increases both of NR2A and NR2C and in the ratio of NR1b/NR1a mRNAs [18].
• Our findings suggest that SAP97/NR2A interaction is regulated by CaMKII-dependent phosphorylation and provide a novel mechanism for the regulation of synaptic targeting of NMDA receptor subunits [19].
• Tyrosine phosphorylation of the NR2A and NR2B subunits of the N-methyl-d-aspartate (NMDA) receptor by Src protein-tyrosine kinases modulates receptor channel activity and is necessary for the induction of long term potentiation (LTP) [20].
• cDNA clones for four different N-methyl-D-aspartate (NMDA) receptor subunits (NMDAR2A-NMDAR2D) were isolated through polymerase chain reactions followed by molecular screening of a rat brain cDNA library [21].

Anatomical context of Grin2a

• 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) [17].
• NMDAR2A and NMDAR2C expressed individually in Xenopus oocytes showed no electrophysiological response to agonists [21].
• Treatment of rat brain slices with Tat-H-Ras depleted NR2A from the synaptic membrane, decreased endogenous Src activity and NR2A phosphorylation, and decreased the magnitude of hippocampal LTP [20].
• Our results show that SAP97 directly interacts with the NR2A subunit of NMDA receptor both in an in vitro "pull-out" assay and in co-immunoprecipitation experiments from homogenates and synaptosomes purified from hippocampal rat tissue [19].
• Specifically, within the ipsilateral hippocampus, NR2A was reduced by 9.9%, 47.9%, 40.8%, and 6.3% on PID1, PID2, PID4, and PID7, respectively [22].

Associations of Grin2a with chemical compounds

• This antibody (NR2A/B) did not cross-react with extracts from transfected cells expressing other glutamate receptor subunits, nor did it label non-neuronal tissues [23].
• The effectiveness of the C1 exon to reduce the higher form of potentiation is modulated by heteromeric assemblies with NR2A heteromers yielding smaller levels of potentiation and a larger C1 exon effect compared with NR2B heteromers [24].
• Cotransfection of H-Ras and Src inhibited Src activity and decreased NR2A tyrosine phosphorylation [20].
• Some of the effects of cyanide on NR1/NR2B receptors may be mediated by the formation of a thiocyanate adduct with a cysteine residue located in NR1 [25].
• In addition, the activity of alphaCaMKII on exogenous substrates, such as syntide-2, and the phosphorylation of NR2A/B subunits of N-Methyl-D-Aspartate receptor was reduced in hippocampal post-synaptic densities of streptozotocin-diabetic rats as compared with control rats [26].
• Whole cell voltage-clamp recordings show that Zn(2+) inhibition of agonist-evoked NMDA receptor currents of NR1/NR2A-transfected HEK 293 cells and cultured cortical neurons is significantly reduced by plasmin treatment [27].

Physical interactions of Grin2a

• 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 [28].
• Accordingly, alphaCaMKII(1-325) competes with both the native PSD-95 and the native kinase itself for the binding to NR2A [29].

Regulatory relationships of Grin2a

• In culture, 25 mM KCl or NMDA rapidly induced NR2A and downregulated NR2B, followed by gradual induction of NR2C [18].
• We showed previously in the somatosensory cortex that the shortening of NMDA receptor kinetics correlates with a developmentally-regulated increase in the NR2A subunit expression [6].
• Only a fraction (approximately 23%) of the SAP102 clusters expressed NR2A, suggesting SAP102 is also associated with other subunits or receptors [30].
• The incubation of PSD with BDNF and NGF induced the phosphorylation of NR2A and B subunits [31].
• In addition, Ser/Ala1289 and Ser/Asp1289 point mutations on the unique CaMKII phosphosite of NR2A did not significantly influence the binding of native alphaCaMKII and PSD-95 to the NR2A C-tail [29].

Other interactions of Grin2a

• In 5 mM KCl, a similar, rapid increase in NR2A was observed, but disappearance of NR2B occurred over a longer time course [18].
• In the cerebellum, in contrast to staining with NR1 antibody, Purkinje cell staining with NR2A/B antibody was low, indicating that these neurons may lack functional NMDA receptors [23].
• Last but not least, in choline acetyltransferase (ChAT)-positive striatal interneurons of PND 14 and adult rats, levels of NR1 and NR2A immunoreactivity was seen to increase [32].
• In addition, double immunofluorescence revealed that the levels of NR1 immunoreactivity increased but the levels of NR2A immunoreactivity were the same in parvalbumin (PV)-positive striatal interneurons of PND 14 and adult rats [32].
• One day following washout, it was observed that PCP treatment caused an increase in NR1, NR2A and Bax polypeptides in the cortex, but had no effect on Bcl-xL [33].

Analytical, diagnostic and therapeutic context of Grin2a

• In Western blots of rat brain, the antibody labeled a single band that comigrated with NR2A and NR2B [23].
• The number, percent, and localization of GnRH perikarya expressing NR1, NR2A, or NR2B were mapped and quantified by double label immunofluorescence microscopy [34].
• Reduced NR2A expression and prolonged decay of NMDA receptor-mediated synaptic current in rat vagal motoneurons following axotomy [35].
• Reductions in the levels of expression of NMDAR1 and NMDAR2A messenger RNAs (NMDAR1: 20.6%; NMDAR2A: 19.7%) were found in the antisense-treated striatal tissues by reverse transcriptase-polymerase chain reaction [36].
• The majority of puncta labelled with each NMDA receptor antibody were GluR2-immunoreactive, which suggests that they were present at synapses, and this was confirmed with electron microscopy for the NR1 and NR2A antibodies [37].

References