Disease relevance of GRIK2

• Comparison between our own and published deletion data singled out GRIK2 as the gene most frequently affected by deletions of 6q in acute lymphocytic leukemia (ALL) [1].
• Refinement of map position of the human GluR6 kainate receptor gene (GRIK2) and lack of association and linkage with idiopathic generalized epilepsies [2].
• Our results indicate that the GluR6-PSD95-MLK3 complex quickly enhanced at 5min of ischemia and peaked at 10min of ischemia, and then gradually reduced with the prolonged time of ischemia [3].
• 1. Whole-cell recordings from cultured rat hippocampal neurons, from freshly dissociated dorsal root ganglion (DRG) neurons and from human embryonic kidney (HEK) 293 cells expressing the glutamate receptor GluR6 subunit were used to study the modulation of kainate receptor channels by long chain fatty acids [4].

Psychiatry related information on GRIK2

• The most surprising negative result is for the GRIK2 (TAA)(n) polymorphism, which has previously shown association with age of onset in four independent populations with Huntington's disease [5].
• We report a complex mutation in the ionotropic glutamate receptor 6 gene (GRIK2, also called "GLUR6") that cosegregates with moderate-to-severe nonsyndromic autosomal recessive mental retardation in a large, consanguineous Iranian family [6].

High impact information on GRIK2

• Site-directed mutagenesis was used to identify the site or sites of phosphorylation on GluR6 [7].
• Although mutagenesis of two serine residues, Ser684 and Ser666, was required for complete abolition of the PKA-induced potentiation, Ser684 may be the preferred site of phosphorylation in native GluR6 receptor complexes [7].
• The functional modulation of GluR6, a kainate-activated glutamate receptor, by adenosine 3',5'-monophosphate-dependent protein kinase A (PKA) was examined with receptors expressed in human embryonic kidney cells [7].
• Here we show that stabilization of the binding domain dimer by the generation of intermolecular disulfide bonds apparently blocked desensitization of the kainate receptor GluR6 [8].
• The structures reveal that the ligand binding cavities are 40% (GluR5) and 16% (GluR6) larger than for GluR2 [9].

Chemical compound and disease context of GRIK2

• The effects of lanthanum and gadolinium on currents evoked by excitatory amino acids were studied in cultured rat hippocampal and cortical neurons, in freshly dissociated dorsal root ganglion neurons, and in human embryonic kidney 293 cells expressing the GluR6 kainate receptor subunit [10].

Biological context of GRIK2

• This localization excludes GRIK2 as a candidate for the putative IGE susceptibility locus "EJM1" on the short arm of chromosome 6 [2].
• The present study tested the hypothesis that allelic variants of GRIK2 contribute to the genetic susceptibility to the common IGEs [2].
• RNA editing at the Q/R site for the glutamate receptor subunits GLUR2, GLUR5, and GLUR6 in hippocampus and temporal cortex from epileptic patients [11].
• We have tested the hypothesis that distinct allosteric binding sites control GluR6 receptors via a common transduction pathway [12].
• Association of a relatively infrequent 16 TAA allele of a trinucleotide repeat polymorphism in the GRIK2 3'UTR with earlier than expected age at neurological onset has been suggested to reflect linkage disequilibrium with a functional polymorphism in GRIK2 or an adjacent gene [13].

Anatomical context of GRIK2

• Among T-cell ALL patients, 6q deletion was associated with a statistically significant reduction in GRIK2 expression (P = 0.0001) [1].
• Finally, we detected significant levels of GRIK2 expression in prostate, kidney, trachea, and lung, raising the possibility that this gene may be protective against multiple tumor types [1].
• GluR6 mRNA was relatively abundant in all areas, notably in dentate gyrus, pyramidal neurons of CA3, and cerebellar granule cells, as well as being present in superficial and deep laminae of the neocortex [14].
• By PCR analysis of rodent-human monochromosomal cell lines, the human GluR6 could be assigned to chromosome 6 [15].
• PEPA (1-200 microM) dose dependently potentiated glutamate-evoked currents in Xenopus oocytes expressing AMPA (GluRA-GluRD), but not kainate (GluR6 and GluR6+KA2) or NMDA (zeta1 + epsilon1-epsilon4), receptor subunits [16].

Associations of GRIK2 with chemical compounds

• Human GluR6 kainate receptor (GRIK2): molecular cloning, expression, polymorphism, and chromosomal assignment [15].
• The rate of desensitization elicited by 10 mM L-glutamate was similar in control (taufast = 5.5 +/- 0.4 ms), Con-A-treated patches (taufast = 6.1 +/- 0.5 ms) and patches containing PSD-95 and GluR6 receptors (taufast = 4.7 +/- 0.6 ms) [12].
• The alteration in GluR5 and GluR6 mRNA editing in the neocortical tissue may reflect an adaptive reaction of ongoing seizure activity to prevent excessive Ca(2+) influx [11].
• Comparison of genomic and cDNA sequences revealed extensive editing of the human EAA4 (GluR6) mRNA at the isoleucine/valine, tyrosine/cysteine sites of the transmembrane I region, and the glutamine/arginine site of the transmembrane II region [17].
• To test the proposed transmembrane topology model for these receptors, we have used site-specific mutagenesis of the GluR6 subunit to remove the consensus glycosylation site located within the proposed intracellular loop [18].

Regulatory relationships of GRIK2

• The GluR5 subunit was expressed in distal dendrites only when GluR6 and KA2 subunits were present, whereas it was restricted to proximal dendrites in the absence of these subunits [19].
• Finally, we determined the C-terminal half of the L3 domain plus the far C-terminal domain of GluR7 to be responsible for the recently reported reduction of current amplitude seen when GluR7 is coexpressed with GluR6 [20].
• By contrast, Rab5 downregulated the currents in oocytes expressing wild type GluR6 but had only little, statistically not significant effects on currents in oocytes expressing GluR6(M836I) [21].
• A retinal-specific regulator of G-protein signaling interacts with Galpha(o) and accelerates an expressed metabotropic glutamate receptor 6 cascade [22].

Other interactions of GRIK2

• Using reverse transcription-PCR, we found evidence of expression in hematopoietic cells for 3 of 15 genes in the region (GRIK2, C6orf111, and CCNC) [1].
• Finally, we found that the IW selectivity for GluR5 compared with GluR6 was determined by amino acid 721, which was previously shown to control alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate sensitivity of these kainate receptor subunits [23].
• We have investigated the subtype selectivity of these compounds by examining their binding affinity for homomeric hGluR1, -2, -4, or -5 (and hGluR6 in the case of 5-iodowillardiine (22)) [24].
• Likewise, the time course of recovery from GluR6 desensitization was similar in both control and Con-A conditions, whereas PSD-95 accelerated recovery almost twofold [12].
• Two other kainate subunit transcripts, GluR6 and KA1 also showed significant changes compared to non-epileptic tissue (136% and 71% of control, respectively) [25].

Analytical, diagnostic and therapeutic context of GRIK2

• Sequence analysis of GRIK2 in 14 ALL cases carrying heterozygous 6q deletions revealed a constitutional and paternally inherited C to G substitution in exon 6 encoding for an amino acid change in one patient [1].
• Our linkage and association results suggest that allelic variants of GRIK2 are not involved in the expression of the common familial IGEs, and radiation hybrid mapping assigns GRIK2 to the chromosomal region 6q16.3-q21 [2].
• Site-directed mutagenesis was used to demonstrate that palmitoylation of GluR6 occurs at two cysteine residues, C827 and C840, located in the carboxyl-terminal domain of the molecule [26].
• Immunoprecipitation studies showed that antibodies to GluR6 and KA2 selectively immunoprecipitated [3H]kainate binding activity, but not 3H-labeled alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) binding activity, from Triton X-100-solubilized rat brain membranes [27].
• Gating was studied using ultra-fast drug perfusion of outside-out patches containing rat GluR-A or GluR6 subunits excised from transfected human embryonic kidney cells [28].

References