Disease relevance of GRIA2

• There were no significant differences in the pattern of relative AMPA subunit expression (GluR2/3 > or = GluR4 > GluR1) between groups of motor neurons typically affected (in the spinal cord and hypoglossal nucleus), or spared (oculomotor and Onufs nucleus) by the amyotrophic lateral sclerosis disease process [1].
• Recent studies involving animal models of transient forebrain ischemia and epilepsy show that GluR2 mRNA and GluR2 subunit expression are downregulated in vulnerable neurons prior to cell death [2].
• GluR2 pre-mRNA in leiomyoma and myometrial tissues is nearly 100% edited at the Q/R site, indicative of low Ca(2+) permeability of the ion channels [3].
• After ischemia treated by hypothermia GluR2 mRNA expression was modestly reduced at 2 days and exhibited complete recovery to control levels at 7 days [4].
• Underediting of glutamate receptor GluR-B mRNA in malignant gliomas [5].

Psychiatry related information on GRIA2

• We used in situ hybridization to examine GluR1, GluR2, and GluR3 messengerRNAs (encoding alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate receptor subunits) in sections of autopsy samples of Alzheimer's disease brains and age-, sex-, and post-mortem delay-matched brains from non-demented (control) subjects [6].
• Significant increases were observed for GluR2 and GluR3 in the hippocampi of subjects with alcohol abuse histories when compared to the non-psychotic normal control group [7].
• Here, we used herpes simplex virus vectors to examine how transient increases in the expression of GluR1 or GluR2 protein in the shell component of NAc affect the rewarding impact of electrical stimulation of the medial forebrain bundle, as reflected by intracranial self-stimulation (ICSS) thresholds in rats [8].
• Disturbances of GluR-2 RNA editing leading to excessive Ca2+ permeability, may contribute to neuronal dysfunction in schizophrenia and to neuronal death in Alzheimer's disease and Huntington's disease [9].
• GluR2/3, NMDAepsilon1 and GABAA receptors in Creutzfeldt-Jakob disease [10].

High impact information on GRIA2

• Using the GluR2 AMPA-sensitive glutamate receptor, we show here that the ligand-binding cores form dimers and that stabilization of the intradimer interface by either mutations or allosteric modulators reduces desensitization [11].
• Thus, the GluR-B editing enzyme may contain the adenosine deaminase, or a similar activity, and an RNA recognition subunit that specifically targets the enzyme to the editing site [12].
• Here we show that the GluR-B pre-mRNA is efficiently and accurately edited in vitro, and that base-pair interactions between the editing site and a sequence in the downstream intron are required for substrate recognition [12].
• The steady-state current-voltage (I-V) relations of glutamate- and kainate-induced currents through homomeric channels fell into two classes: channels composed of either the GluR-A, -C, and -D subunits showed doubly rectifying I-V curves, and channels composed of the GluR-B subunits displayed simple outward rectification [13].
• The properties of heteromeric wild-type and mutant GluRs revealed that the dominance of GluR-B is due to the arginine residue in the TM2 region [13].

Biological context of GRIA2

• Southern and PCR analysis of a somatic cell-hybrid panel mapped HBGR1 to human chromosome 5q31.3-33.3 and mapped HBGR2 to chromosome 4q25-34 [14].
• RNA editing (R/G site) and flip-flop splicing of the AMPA receptor subunit GluR2 in nervous tissue of epilepsy patients [15].
• This result suggests that modulation of serine-880 phosphorylation in GluR2 controls the clustering of AMPA receptors at excitatory synapses and consequently contributes to synaptic plasticity [16].
• The study shows that desensitization and resensitization kinetics of homomeric GluR2 flop channels are controlled by a single amino acid exchange (glycine by arginine) at the R/G site [17].
• To examine whether acute GluR2 downregulation, even in the absence of a neurological insult, can induce neuronal death, we performed knockdown experiments in rats and gerbils with antisense oligonucleotides targeted to GluR2 mRNA [2].

Anatomical context of GRIA2

• The absence of detectable GluR2 mRNA in normal human spinal motor neurons predicts that they express calcium-permeable AMPA receptors unlike most neuronal groups in the human CNS [18].
• Most native AMPA receptors in the mammalian central nervous system (CNS) contain the GluR2 subunit and are calcium impermeable [18].
• RNA editing at the Q/R site for the glutamate receptor subunits GLUR2, GLUR5, and GLUR6 in hippocampus and temporal cortex from epileptic patients [19].
• In contrast, Bergmann glial cells in rat cerebellum do not express GluR2 (GluR-B) subunit genes [20].
• GluR2 mRNA was at high density in the dentate gyrus and in CA3, but was at low density in CA1, subiculum, and entorhinal cortex [6].

Associations of GRIA2 with chemical compounds

• Uniquely, the loop 1 (L1) regions between hydrophobic domain 1 and hydrophobic domain 2 of the hagfish putative GRIA2 and all the teleost GRIA1 subunits were much longer than those of the remaining known ionotropic glutamate receptor subunits [21].
• However, in rhesus monkeys chronically treated with antipsychotic drugs, clozapine treatment significantly decreased GRIA1 and increased GRIA3 mRNA expression, while both clozapine and haloperidol increased the expression of GRIA2 subunit mRNA [22].
• Isoforms DRADA2c and -2d, which have a distinctive truncated shorter C-terminal structure, displayed weak adenosine-to-inosine conversion activity but no editing activity tested at three known sites of GluR-B RNA [23].
• However, correcting for changes in neuron densities showed that hippocampal sclerosis patients had increased AMPA and NMDA mRNA levels per neuron compared with autopsies, and in the CA2 resistant sector GluR2 mRNA levels were numerically greater than autopsies and mass lesion cases [24].
• 5-Fluorowillardiine (19) has higher affinity than AMPA for both homomeric hGluR1 and hGluR2 and compared to AMPA displays greater selectivity for AMPA receptor subtypes over the kainate receptor, hGluR5 [25].

Physical interactions of GRIA2

• Phosphorylation of serine-880 in GluR2 by protein kinase C prevents its C terminus from binding with glutamate receptor-interacting protein [16].
• GluR2 might be coupled to this synergism directly or via interleukin-17B, kinesin KIF5 or related genes also up-regulated in leiomyomata [3].
• Adenosine to inosine editing by ADAR2 requires formation of a ternary complex on the GluR-B R/G site [26].
• This structure will predominate if GluR1 binds to GluR2 more rapidly during receptor assembly than other subunit combinations [27].
• The AMPA-subclass glutamate receptor GluR2 interacts with the membrane-fusion protein NSF in a manner that appears important for receptor-mediated intracellular signalling [28].

Enzymatic interactions of GRIA2

• Editing of the human GluR-B transcript is catalyzed by the enzyme ADAR2 at the Q/R and R/G sites [26].
• Pretreatment with WAY-100635 counteracted the NBQX effects and restored the initial learning-specific increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) function and the later increase in GluR2/3 and phosphorylated GluR1 surface expression [29].

Co-localisations of GRIA2

• Immunostaining of cultured hippocampal neurons demonstrates that the Ser880-phosphorylated GluR2 subunits are enriched and colocalized with PICK1 in the dendrites, with very little staining observed at excitatory synapses [30].

Regulatory relationships of GRIA2

• These results suggest that Q/R site of GluRs editing is regulated in a regional, and hence presumably cell-specific, manner and that the GluR2 Q/R site editing is critically regulated by ADAR2 in human brain [31].
• The NMDA-induced GluR2 internalization was also observed in the absence of extracellular Na+ ions, suggesting that membrane depolarization is not a prerequisite for this effect [32].
• NMDA-induced GluR2 endocytosis was completely inhibited by pharmacological block of NR2B-containing NMDARs [32].
• The L-glutamate EC50 was 10.2 microM when wild-type GluR-A was coexpressed with GluR-B (GluR-A/B) and 38.9 microM when GluR-A445Q/B449Q receptors were tested [33].
• These results implicate GluR2-lacking AMPA receptors in the ischemia-induced rise in free Zn(2+) and death of CA1 neurons, although a direct action at the time of the rise in Zn(2+) is unproven [34].

Other interactions of GRIA2

• As originally reported for rat RED1, the DRADA2a and -2b isoforms edit GluR-B RNA efficiently at the so-called Q/R site, whereas DRADA1 barely edits this site [23].
• Furthermore, GluR2/3 immunoreactivity had principally a somatic distribution whereas GluR5/6/7 labeling was predominately found in the perikarya and/or particular dendritic domains [35].
• The GluR2 flip G variant showed the slowest desensitization (10.8 ms), GluR4 flip the fastest (1.6 ms) [36].
• Interestingly, PKC activation in neurons increases the Ser880 phosphorylation of GluR2 subunits and recruits PICK1 to excitatory synapses [30].
• Another case of RNA editing alters an arginine (R) to a glycine (G) codon at a position termed the "R/G" site of AMPA subunits GluR-B, C, and D. Double-stranded RNA-specific adenosine deaminases (DRADA) have been implicated as agents involved in the editing [37].

Analytical, diagnostic and therapeutic context of GRIA2

• Furthermore, both the expression level and the proportion of GluR2 mRNA in motoneurons were the lowest among all neuronal subsets examined, whereas those in motoneurons of ALS did not differ from the control group, implying that selective reduction of the GluR2 subunit cannot be a mechanism of AMPA receptor-mediated neurotoxicity in ALS [38].
• We used patch-clamp techniques with ultrafast solution exchange to examine the kinetics of recombinant human homomeric GluR2 flop channels transiently expressed in HEK293 cells [edited at the R/G site and Q/R/N site (GR), and unedited (RN) and edited (GN) at the R/G site both with asparagine (N) at the Q/R/N site] [17].
• New potential regulators of uterine leiomyomata from DNA arrays: the ionotropic glutamate receptor GluR2 [3].
• We assessed GluR2 protein expression in the BLA by immunocytochemistry with a GluR2 subunit-specific antiserum at the light and electron microscopic level; for comparison, a parallel examination was carried out in the hippocampus [39].
• Immunohistochemical and double immunofluorescence results showed that the GluR2/3 were mainly expressed and co-localized with OX-42-positive microglia/macrophages and the glial fibrillary acidic protein (GFAP)-positive astrocytes [40].

References