Disease relevance of Grik2

• Neuroprotective effects of GluR6 antisense oligodeoxynucleotides on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 region [1].
• To investigate whether the kainate (KA) receptors subunit GluR6 is involved in the neuronal cell death induced by cerebral ischemia followed by reperfusion, the antisense oligodeoxynucleotides (ODNs) of GluR6 were used to suppress the expression of GluR6 by intracerebroventricular infusion once per day for 3 days before ischemia [1].
• Results indicate that mRNA editing is regulated differently in each of the glutamate receptor subunits GluR2, GluR5, and GluR6 after transient cerebral ischemia [2].
• The GluR6 subunit was expressed in a more restricted manner in the ganglion cell layer [3].
• Intra-amygdaloid injections of KA provide a model of temporal lobe epilepsy, and we show that following seizures, the extent of GluR5 and GluR6 editing is altered in the hippocampus [4].

Psychiatry related information on Grik2

• 7. The effects of both calcineurin and PKA on Po,peak for GluR6 receptors in excised patches occur without any detectable changes to response time course, desensitization, or chord conductance [5].

High impact information on Grik2

• Here we report that the GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response [6].
• Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase [6].
• The pharmacological profile was independent of AMPA receptors or the GluR5 subunit, indicating a possible role for the GluR6 subunit [7].
• These data suggest how KARs, putatively containing GluR6, directly increase excitability of CA1 pyramidal cells and help explain the propensity for seizure activity following KAR activation [7].
• In addition, we show that the Q/R site from the GluR6 subunit controls functional properties of native kainate receptors [8].

Chemical compound and disease context of Grik2

• In conclusion, our results demonstrate that kainate receptor subunit GluR6 plays an important role in neuronal death induced by cerebral ischemia followed by reperfusion [1].
• Solubilization of the kainic acid receptor GluR6/7 and the PSD-95 binding proteins, neuronal nitric oxide synthase and p135synGAP, also decreased following ischemia [9].
• Here, we try to find out whether brain ischemia and reperfusion could induce any change in the serine phosphorylation of GluR6 [10].

Biological context of Grik2

• The C terminus of GluR6, RLPGKETMA-oh, lacking the consensus sequence, binds to PDZ1 of SAP90 with an affinity of 160 microm [11].
• The effects of GluR6 antisense ODNs on the phosphorylation of MLK3 and JNK and the interactions of MLK3 and PSD-95 with GluR6 were examined by immunoprecipitation and immunoblotting [1].
• On the other hand, the GluR6 antisense ODNs also show a protective role against neuronal cell death induced by cerebral ischemia/reperfusion [1].
• CONCLUSIONS: KA-induced SE leads to an upregulation of GluR5 mRNA and protein and a downregulation of GluR7 mRNA in rat hippocampus, with no change in GluR6 mRNA or protein expression [12].
• RNA editing of glutamate receptor subunits GluR2, GluR5 and GluR6 in transient cerebral ischemia in the rat [2].

Anatomical context of Grik2

• Our results provide evidence for the existence of functional glutamate receptors of the kainate type in nerve cells, which are likely to be native homomeric GluR-6 receptors [13].
• GluR-6 mRNA is most abundant in cerebellar granule cells, with lower levels in caudate-putamen and the pyramidal cell layers and dentate granule cells of hippocampus [14].
• These results suggest that GluR6/7 subunits of KA receptors may be constitutively expressed with responsiveness to the systemic administration of an agonist at least in the rat adenohypophysis [15].
• Immunoreactive GluR6/7 subunits were only detectable in the adenohypophysis, but not in the adrenal cortex, adrenal medulla and neurohypophysis [15].
• GluR6 was highly expressed in the striatum and subthalamic nucleus and to a lesser extent in the substantia nigra pars reticulata, while no hybridization signal was detectable in the large, presumably dopaminergic neurons of the substantia nigra pars compacta [16].

Associations of Grik2 with chemical compounds

• We report the crystal structure of the glycosylated ligand-binding (S1S2) domain of the kainate receptor subunit GluR6, in complex with the agonist domoate [17].
• Subtle differences in these contacts provide a structural explanation for why GluR2 L483Y and GluR3 L507Y are nondesensitizing, but GluR6, which has a tyrosine at that site, is not [17].
• Structure of the kainate receptor subunit GluR6 agonist-binding domain complexed with domoic acid [17].
• The EC50 for receptor activation by 2S,4R-4MG (1.0 microM) was similar to that for kainic acid (1.8 microM), but 2S,4R-4MG was significantly more potent than kainate, glutamate or the other diastereomers of 4-methylglutamate at producing steady-state desensitization of GluR6 receptors [18].
• The potencies of kainate, glutamate and diastereomers of 4-methylglutamate were determined for activation and steady-state desensitization of GluR6 and dorsal root ganglion-type kainate receptors using whole-cell voltage clamp [18].

Physical interactions of Grik2

• Kainate receptor glutamate receptor 6 (GluR6) binds to the postsynaptic density protein 95 (PSD-95), which in turn anchors mixed lineage kinase 3 (MLK3) via SH3 domain in rat brain tissue [19].

Regulatory relationships of Grik2

• Our results indicate that although GluR6 is primarily expressed by pyramidal cells and dentate granule neurons and GluR5 is prominently expressed in nonpyramidal cells, there is a significant population of GABAergic interneurons that coexpress the two glutamate receptor subunits [20].
• The kainate-selective glutamate receptor GluR6 was constitutively expressed under the control of a metallothionein promoter [21].

Other interactions of Grik2

• At a moderate level were GluR6, NR2B, and NR2D [22].
• All four AMPA subunits and GluR6 and GluR7 mRNAs were expressed highly in the perinuclear PVN region and the subparaventricular zone [23].
• Differently, Glur6 and KA2 mRNAs show a sharp increase at E14.5 and decrease thereafter, reaching the lowest levels during late embryonic and postnatal development [24].
• In common with the AMPA receptor subunit GluR2, the GluR6 S1S2 domain associates as a dimer, with many of the interdimer contacts being conserved [17].
• Low levels of GluR1, GluR4 and GluR6 expression were detected in various tissues of the cochlea during development [25].

Analytical, diagnostic and therapeutic context of Grik2

• Western blot showed an increase in GluR6 protein levels (P<0.01) with a time course consistent with the changes in its mRNA levels. cDNA sequence and BbvI endonuclease digestion of the GluR6 PCR product revealed that the upregulated GluR6 mRNAs were predominantly the unedited form (Q) [26].
• Polymerase chain reaction studies showed that the glutamate receptor subunits GluR1-4 and GluR6 were all expressed in these cultures, but GluR5 was absent [27].
• The rat hippocampal neurons in the cultures were shown to express kainate receptor subunits, KA2 and GluR6/7, either by immunocytochemistry or by immunoblot analysis [28].
• KA receptors, e.g. GluR5 and GluR6 have been characterized by molecular cloning [4].
• Larger intercellular variation in (Q/R) editing of GluR6 than GluR5 revealed by single cell RT-PCR [29].

References