Disease relevance of GRIN2A

• Distribution of the N-methyl-D-aspartate glutamate receptor subunit NR2A in control and amyotrophic lateral sclerosis spinal cord [1].
• N-Methyl-D-Aspartate (NMDA) receptors containing NR1 and NR2A subunits have been expressed with high efficiency in Human Embryonic Kidney 293 cells with the aid of a recombinant vaccinia virus [2].
• INTERPRETATION: Antibodies to NR2B- and NR2A-containing heteromers of the NMDAR associate with a severe but treatment-responsive encephalitis [3].
• METHODS: Autoantibodies to NR2A/2B were measured in 360 serum samples: 105 from TIA/stroke patients and 255 from controls, including patients with controlled hypertension/atherosclerosis and gender- and age-matched healthy individuals [4].
• We investigated the diagnostic accuracy of serum aAbs to NR2A/2B, a subtype of NMDA receptors, in assessing transient ischemic attack (TIA) and ischemic stroke (IS) and its ability to distinguish cerebral ischemia from intracerebral hemorrhage (ICH) [4].

Psychiatry related information on GRIN2A

• Owing to the role of GRIN2A in aspects of cognition, we investigated the relationship of this gene to the cognitive phenotypes of inhibitory control, verbal short-term memory and verbal working memory [5].
• Glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene as a positional candidate for attention-deficit/hyperactivity disorder in the 16p13 region [5].
• CONCLUSIONS: GRIN2A and TCERG1 may show true association with residual age of onset for Huntington's disease [6].
• N-methyl-D-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippocampus and entorhinal cortex in Alzheimer's disease [7].
• Genetic analysis of a functional GRIN2A promoter (GT)n repeat in bipolar disorder pedigrees in humans [8].

High impact information on GRIN2A

• In this model, different NMDA receptor scaffolding and signaling complexes effect the trafficking and synaptic localization of NR2A-rich and NR2B-rich receptors, leading to tangential compartmentalization of these receptors and their movement between synaptic and extrasynaptic compartments [9].
• In cell systems expressing NMDARs with mutant NR2A subunits in which this single cysteine was replaced by an alanine, the effect of endogenous NO was lost [10].
• Using site-directed mutagenesis, we have identified three C-terminal tyrosine residues of NR2A that are required for Src's modulation of the zinc sensitivity of NMDA receptors [11].
• Switching synaptic NR2B-containing NMDA-Rs that bind CaMKII with high affinity with those containing NR2A, a subunit with low affinity for CaMKII, dramatically reduces LTP [12].
• In studying chimeras of NR2A and NR2C subunits of the NMDA receptor, we have found that glycine-independent desensitization depends on two regions of the extracellular N-terminal domain [13].

Chemical compound and disease context of GRIN2A

• In contrast, ischemia of longer duration (up to 30 min) caused an immediate decrease in the protein levels as well as tyrosine phosphorylation of both NR2A and NR2B subunits which was accompanied by the marked attenuation of the association with their investigated molecular partners--PSD-95 and NRTKs [14].

Biological context of GRIN2A

• There was no significant evidence of linkage between GRIN2A and these phenotypes [5].
• Our data suggest that genetic variation in GRIN2A may confer increased risk for ADHD and that this, at least in part, might be responsible for the linkage result on 16p reported by Smalley et al [15].
• We tested for linkage between the alleles and haplotypes of four polymorphisms at the GRIN2A locus and ADHD in our sample of 183 nuclear families with 229 affected children [5].
• Analysis of the GRIN2A gene detected four single nucleotide polymorphisms, and a variable (GT)(n) repeat in the promoter region of the gene [16].
• A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia [16].

Anatomical context of GRIN2A

• NR1- and NR2A/B-positive neurons were mostly pyramidal cells, but some nonpyramidal neurons were also labeled [17].
• Neuronal and glial localization of NR1 and NR2A/B subunits of the NMDA receptor in the human cerebral cortex [17].
• In addition, both NR1 and NR2A/B were consistently found in the axoplasm of some axon terminals and in distal astrocytic processes [17].
• We also report the expression and pharmacological characterisation of recombinant human NR1a/NR2A heteromeric receptors in Xenopus oocytes [18].
• Giant neurons of the deep dorsal cochlear nucleus were the most conspicuous somata stained by the NR2A [19].

Associations of GRIN2A with chemical compounds

• The glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the NMDA receptor, resides in this region and a recent study has reported an association between this gene and ADHD [5].
• The GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) gene that encodes the N-methyl D-aspartate receptor subunit 2A (NMDA2A) maps to this region of linkage [15].
• Analysis of correlation between serum D-serine levels and functional promoter polymorphisms of GRIN2A and GRIN2B genes [20].
• Although the carboxy(C)-terminal domain of the NR2A subunit contains potential tyrosine phosphorylation sites, the mechanisms by which Src modulates synaptic plasticity and NMDA receptor currents is not fully understood [11].
• Glycine antagonist sites with low and intermediate affinity for [3H]CGP 61594 were detected also in situ by radioligand binding in brain areas predominantly expressing the NR2A and NR2C subunits, respectively [21].

Physical interactions of GRIN2A

• We have localized regions in the S1 binding domain of both subunits required for the transmission of allosteric signals from the glutamate binding NR2A subunit to the glycine binding NR1 subunit [22].
• Ser39 phosphorylation does not interfere with SAP97 capability to bind NR2A [23].

Regulatory relationships of GRIN2A

• In contrast to the null effects of con-G and Ala/con-G at a NR1a/NR2A-containing receptor, some inhibition ( approximately 40%) of NMDA-evoked currents was effected by these peptides in cells expressing NR1b/NR2A [24].
• Thus, CaMKII-dependent phosphorylation of SAP97 in different time frames and locations within the neurons controls both NR2A trafficking and insertion [23].
• However, NR2A/B and 8-OHdG immunoreactivities were enhanced in CA1 over 24 h after ischemia although NR1 immunoreactivity was decreased [25].

Other interactions of GRIN2A

• HS patients, by comparison, showed decreased pyramidal neuron NR2A mRNA levels, and this suggests that NMDA-mediated pyramidal neuron responses should be reduced in HS patients compared with non-HS cases [26].
• Compared with autopsy hippocampi, non-HS and HS patients showed increased NR2A and NR2B hybridization densities per dentate granule cell [26].
• In addition, GRIN2A and GRM6 loci were successfully localized on Chr 10 linkage maps by linkage analyses [27].
• We conclude that replication is required and that further work examining for association of GRIN2A polymorphisms with ADHD is warranted [15].
• HS patients, by contrast, showed decreased NR2A hybridization densities per CA2/3 pyramidal neuron compared with non-HS and autopsy cases [26].

Analytical, diagnostic and therapeutic context of GRIN2A

• Recently, we identified a variable (GT)n repeat in the promoter region of the NMDA NR2A subunit gene (GRIN2A), and showed its association with schizophrenia in a case-control study, together with a correlation between the length of the repeat and severity of chronic outcome [28].
• Immunoblotting of the double immunopurified NR2A/NR2B(FLAG)-containing material demonstrated the presence of anti-NR1, anti-NR2A, anti-FLAG, and, more important, anti-c-Myc antibody immunoreactivities [29].
• Amino acid residues positioned at or near the narrow constriction that interact with intracellular Mg2+ were identified in recombinant NR1-NR2A channels expressed in Xenopus oocytes or human embryonic kidney (HEK) 293 cells [30].
• The oligomerization status of the co-expressed NR1a constructs and NR2A subunits was investigated using a non-denaturing gel electrophoresis system (blue native-polyacrylamide gel electrophoresis) and sucrose density gradient centrifugation [31].
• Western blot analysis confirmed a lower expression of the NR2A and NR2B isoforms at the protein level [32].

References