Disease relevance of Gria2

• Following global ischemia, the levels of GluR-B flip and flop variants are dramatically reduced (90-100%), well before any morphological signs of cell death, in the subiculum and CA1, two areas known to be particularly sensitive to ischemic insult [1].
• Using in situ hybridization techniques, we show that kainate-induced epilepsy provokes a rapid but transient increase (50%) of GluR-B flip mRNA levels in all subregions of the hippocampus (CA1, CA3, dentate gyrus) [1].
• However, no evidence was found for a preferential loss of GluR2 immunoreactivity that could account for selective neurodegeneration of amacrine and ganglion cells after retinal ischemia [2].
• Pretreatment of cultures with botulinum toxin E or tetanus toxin prevents the receptor insertion into the plasma membrane, whereas treatment with alpha-latrotoxin enhances the surface exposure of GluR2, both in growth cones of cultured neurons and in brain synaptosomes [3].
• When GluR2 promoter activity was investigated by plasmid transfection into cultured cortical neurons, cortical glia, and C6 glioma cells, the promoter construct with the strongest activity, per transfected cell, was 29.4-fold (+/- 3.7) more active in neurons than in non-neural cells [4].

Psychiatry related information on Gria2

• None of these increases occurred in the rats exposed to daily cocaine that did not develop behavioral sensitization (<20% increase in motor activity), and no changes were measured in the level of GluR2/3 in any treatment group [5].
• The antidepressant-induced increase in the number of GluR1- and GluR2/3-containing AMPARs at the synapses may indicate an enhanced AMPAR-mediated synaptic transmission which could help to counteract the alterations in neuronal connectivity which appear to underlie the pathophysiology of mood disorders [6].

High impact information on Gria2

• Indeed, viral-mediated overexpression of both GluR1 and GluR2 in nucleus accumbens shell neurons facilitates extinction of cocaine- but not sucrose-seeking responses [7].
• We analysed the lateral mobility of native AMPA receptors containing the glutamate receptor subunit GluR2 in rat cultured hippocampal neurons, using single-particle tracking and video microscopy [8].
• These properties have allowed us to follow directly the involvement of GluR2 subunits in synaptic transmission [9].
• Both deaminases edit the R/G site in GluR-B pre-mRNA, indicating that members of an emerging gene family catalyse adenosine deamination in nuclear transcripts with distinct but overlapping substrate specificities [10].
• Notably, Bergmann glial cells in the cerebellum have Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) assembled without the GluR2 subunit [11].

Chemical compound and disease context of Gria2

• Alterations of the GluR-B AMPA receptor subunit flip/flop expression in kainate-induced epilepsy and ischemia [1].
• To demonstrate the cellular distributions of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor subunits (GluR1, GluR2/3, and GluR4) in the intrastriatal grafts of a rat model of Parkinson's disease, immunocytochemistry was performed in 6-hydroxydopamine rats with intrastriatal transplants of fetal ventral mesencephalon (VM) [12].
• These changes could lead to formation of GluR2-lacking, Ca(2+)-permeable AMPA receptors and increased toxicity of endogenous glutamate [13].
• Reduction in GluR2 subunit expression and subsequent increases in AMPA receptor mediated Ca(2+) currents were postulated to exacerbate glutamate neurotoxicity following seizures or global ischemia [14].
• In adult rats, kainic acid-induced status epilepticus markedly reduces GluR2 (the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, AMPA subunit that limits Ca2+ permeability), receptor mRNA in the vulnerable CA3 and may contribute to delayed neurodegeneration [15].

Biological context of Gria2

• These results indicate that Ser-696 of GluR2, or the corresponding sites in other AMPA receptor subunits, is a specific site at which phosphorylation takes place when AMPA-type GluRs are activated by agonists, especially under the influence of certain second messenger activities [16].
• Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD [17].
• Furthermore, the increase in hypothalamic GluR 2/3 levels was two times higher in females, compared with males, whereas the changes in hypothalamic GluR 1 levels showed no sex differences [18].
• Ventral root avulsion leads to downregulation of GluR2 subunit in spinal motoneurons in adult rats [19].
• Regulation of kinetic properties of GluR2 AMPA receptor channels by alternative splicing [20].

Anatomical context of Gria2

• After AMPA-induced internalization, homomeric GluR2 enters the recycling pathway, but following NMDA, GluR2 is diverted to late endosomes/lysosomes [21].
• Neurons receiving synaptic input from the auditory nerve, including globular, round, spherical, and fusiform cells, expressed GluR2, GluR3, and GluR4 subunits [22].
• The regulatory effect of estradiol on AMPA receptors was found to be site and gender specific: after estradiol treatment, samples taken from the hypothalamus contained increased levels of GluR1 and GluR2/3, whereas in the septum, bed nucleus and amygdala, no changes could be detected [18].
• AMPA receptors in the rat and primate hippocampus: a possible absence of GluR2/3 subunits in most interneurons [23].
• This early phase is followed by a second, persistent GluR-B flip increase in regions in which neurons are known to be seizure-resistant (i.e. CA1 an dentate gyrus) while a 35% decrease is observed in the vulnerable CA3 area [1].

Associations of Gria2 with chemical compounds

• Here we show that extinction training during withdrawal from chronic cocaine self-administration induces experience-dependent increases in the GluR1 and GluR2/3 subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward [7].
• Three closely related genes, GluR1, GluR2, and GluR3, encode receptor subunits for the excitatory neurotransmitter glutamate [24].
• To test this hypothesis, first, the coexpression of dl-alpha-amino-3-hydroxy-5-methyl-4-isoxazone-propionate (AMPA) GluR1, GluR2/3, and androgen receptors or estrogen receptors was revealed in the same cells of septal, amygdaloid, and hypothalamic areas by double immunocytochemistry [18].
• In this specific brain subregion an increase of GluR-3 mRNA level is induced 12 h after LiCl/pilocarpine treatment, while a clear decrease in GluR-1 mRNA level and no significant change in GluR-2 mRNA level can be observed in the same area under these experimental conditions [25].
• In contrast, most of the choline acetyltransferase-immunoreactive cholinergic interneurons were found to display GluR2 immunoreactivity but less GluR1 and no GluR2/3 immunoreactivity in PND21 and adult rats [26].

Physical interactions of Gria2

• Co-immunoprecipitation using anti-Pick1 antibodies revealed that the overexpressed GluR2 C-terminal decoy indeed prevented Pick1 from interacting with the endogenous GluR2/3 [27].
• The glutamate receptor-interacting protein GRIP1 is present in glutamatergic synapses and interacts with the GluR2/3/4c subunits of the AMPA receptors [28].
• Here, we show that N-ethylmaleimide-sensitive fusion protein (NSF) interacts directly and selectively with the intracellular C-terminal domain of the GluR2 subunit of AMPA receptors [29].
• More importantly, calpain activation resulted in the disruption of GRIP binding to the GluR2 subunit of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors [30].
• Using antibodies against the ionotropic glutamate receptor GluR2 and the calcium binding protein calretinin we found two populations of UBCs [31].

Regulatory relationships of Gria2

• GluR2 expression in GnRH neurones did not change over time and was not affected by age; however, the percentage of Fos-positive GnRH neurones expressing GluR2 increased earlier and was sustained from 08.00-16.00 h in young rats whereas, in MA-PE rats, this percentage peaked at 20.00 h [32].
• GluR1-/GluR2-expressing neurons and GluR1-expressing/GluR2-undetectable neurons comprised approximately 1/10 each [33].
• The up-regulation of GluR3 mRNA in this model may cause a molecular change that induces the selective vulnerability of motor neurons to KA by increasing the proportion of GluR2-lacking (i.e. calcium-permeable) AMPA receptors [34].
• During the following 2 weeks, GluR2/3 receptors were downregulated in exchange for GluR4 receptors [35].
• (3) Thirty-eight percent of GluR1- and 28% of GluR2/3-labeled cells express calbindin [36].

Other interactions of Gria2

• Granule cells, previously not known to receive glutamatergic input, expressed GluR2 and GluR4 subunits [22].
• NMDA receptors interact via their NR2 subunits with PSD-95/SAP90 family proteins, whereas AMPA receptors bind via their GluR2/3 subunits to glutamate receptor-interacting protein (GRIP), AMPA receptor-binding protein (ABP), and protein interacting with C kinase 1 (PICK1) [37].
• With the exception of calbindin-positive interneurons, GluR2/3 was absent from hippocampal interneurons in both rat and monkey [23].
• In a previous immunocytochemical study, an unexpected colocalization was reported [W. Kamphuis et al. (2003) J. Comp. Neurol., 455, 172-186] of mGluR6 with the ionotropic AMPA-type glutamate receptor subunit GluR2 in rod bipolar cells of rat retina [38].
• Quantification of the transcript levels demonstrated that mGluR6 and GluR2 genes are expressed at similar levels in rod ON-type bipolar cells [38].

Analytical, diagnostic and therapeutic context of Gria2

• The thermodynamics of binding of the antagonists (S)-NS1209, DNQX and (S)-ATPO to the GluR2 ligand-binding core have been determined by displacement isothermal titration calorimetry [39].
• GluR1 and GluR2/3 expression was assessed by Western blots [18].
• At the transcript level, in situ hybridizations demonstrated abundant GluR2 expression over the complete width of the INL [40].
• Antisera recognizing phosphorylated AMPA receptor subunits at GluR2 Ser-696 or the homologous sites of GluR1/3/4 were produced, and the specificity of one of them, named 12P3, was established by enzyme-linked immunosorbent assay (ELISA), immunoblot and immunoprecipitation analyses [41].
• Evidence that these puncta represented synaptic receptors was obtained with electron microscopy and by examining the association of GluR2- and GluR1-immunoreactive puncta with glutamatergic boutons (identified with vesicular glutamate transporters or markers for unmyelinated afferents) [42].

References