Disease relevance of GRIK1

• The gene encoding the glutamate receptor subunit GluR5 is located on human chromosome 21q21.1-22.1 in the vicinity of the gene for familial amyotrophic lateral sclerosis [1].
• In addition, dosage imbalance of GLUR5 may have a role in the trisomy 21 (Down syndrome) [2].
• Gene structure of the human metabotropic glutamate receptor 5 and functional analysis of its multiple promoters in neuroblastoma and astroglioma cells [3].
• LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine [4].
• To characterize the human GLUR5 gene, which is located on human chromosome 21q22.1, we isolated cDNAs, genomic phage lambda clones, and yeast artificial chromosomes (YACs) and developed sequence tagged sites (STSs) and simple sequence length polymorphisms (SSLPs) for GLUR5 [5].

Psychiatry related information on GRIK1

• Anthropometric indices and life style practices of the indigenous Orang Asli adults in Lembah Belum, Grik of Peninsular Malaysia [6].

High impact information on GRIK1

• We find that LY382884 is a selective antagonist at neuronal kainate receptors containing the GluR5 subunit [7].
• We have used these agents to show that kainate receptors, comprised of or containing GluR5 subunits, regulate synaptic inhibition in the hippocampus, an action that could contribute to the epileptogenic effects of kainate [8].
• A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission [8].
• The structures reveal that the ligand binding cavities are 40% (GluR5) and 16% (GluR6) larger than for GluR2 [9].
• The binding of AMPA- and GluR5-selective agonists to GluR6 is prevented by steric occlusion, which also interferes with the high-affinity binding of 2S,4R-4-methylglutamate to AMPA receptors [9].

Biological context of GRIK1

• Supportive evidence for linkage to a JAE related IGE spectrum (Zmax = 1.67 at GRIK1) under an autosomal dominant mode of inheritance and significant allele sharing (P < 0.05) among the affected family members suggest that allelic variants of GRIK1 contribute a major genetic determinant to the pathogenesis of JAE-related phenotypes [10].
• A tetranucleotide repeat polymorphism in the non-coding region of the kainate-selective GluR5 receptor gene (GRIK1) on chromosome 21q22.1 provides the tool to investigate this candidate gene [10].
• The present association and linkage study tested the hypothesis that allelic variants of GRIK1 confer genetic susceptibility to the pathogenesis of JAE [10].
• Our family-based association analysis using the haplotype-based haplotype relative risk statistic revealed an association of JAE with the nine-repeat containing allele of the GRIK1 tetranucleotide polymorphism (chi2 = 8.31, df = 1, P = 0.004) [10].
• Genomic organization, proposed alternative splicing mechanisms, and RNA editing structure of GRIK1 [11].

Anatomical context of GRIK1

• Potential alterations in glutamate-utilizing excitatory circuits in resected human epileptogenic frontal and temporal neocortex were investigated by using immunocytochemical methods to visualize receptor subunits which comprise the AMPA/kainate (GluR2/3) and kainate (GluR5/6/7) receptor subtypes [12].
• Together with the demonstration that GluR5 transcripts are expressed in the ventral horn of the spinal cord, the region in which susceptible motor neurons reside, the chromosomal localization suggests that a mutated GluR5 gene may be responsible for the familial form of ALS [1].
• Southern hybridization of DNA isolated from mapping panels of Chinese hamster-human hybrid cell lines and high-resolution in situ suppression hybridization localize the GluR5 gene to chromosome 21q21.1-22 [1].
• Cell surface expression of GluR5 kainate receptors is regulated by an endoplasmic reticulum retention signal [13].
• The data indicate that the regional and cellular distribution of KA receptor subunit mRNAs in human hippocampus, neocortex and cerebellum largely parallels that in the corresponding areas of rat brain, albeit at lower levels, especially with regard to GluR5 and KA1 transcripts [14].

Associations of GRIK1 with chemical compounds

• In the present study, we report the genomic reconstruction of the glutamate receptor GluR5 gene (GRIK1, alias GLUR5; 402 kb) by the use of the data available in public databases [11].
• 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 [15].
• Editing of the glutamine/arginine site was also confirmed for EAA3 (GluR5), which displays a significantly higher extent of editing in specific human brain regions compared with rodent whole brain [16].
• In one case, the editing changes a gene-encoded glutamine (Q) to an arginine (R) codon located in the channel-forming domain of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunit GluR-B and also the kainate receptor subunits GluR5 and GluR6 [17].
• It would appear that quite large lipophilic substituents at the 5-position of the uracil ring not only are accommodated by hGluR5 receptors but also lead to enhanced affinity for these receptors [18].

Regulatory relationships of GRIK1

• 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].

Other interactions of GRIK1

• 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 [20].
• 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 [21].
• IW potently elicited currents from glutamate receptor 5 (GluR5)-expressing cells, but showed no activity on homomeric GluR6 or GluR7 receptors [21].
• GluR5/KA-2 receptors had a higher EC50 value than homomeric GluR5 and exhibited a much faster recovery from desensitization [21].
• Allelic association of juvenile absence epilepsy with a GluR5 kainate receptor gene (GRIK1) polymorphism [10].

Analytical, diagnostic and therapeutic context of GRIK1

• Two prodrugs of potent and selective GluR5 kainate receptor antagonists actives in three animal models of pain [22].
• Following RT-PCR with GluR5 primers, all Purkinje cells (n = 6) yielded the expected PCR product, whereas it was not generated from any of the granule cells (n = 5) [23].
• Immunocytochemistry with antibodies specific for glutamate receptors GluR1, GluR2(4) (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid), GluR5/6/7 (kainate) and NR1 (N-methyl-D-aspartate) receptor subunits demonstrated that virtually all projection neurons in all subfields contained subunits from each receptor class [24].
• In general, GluR 5/6/7-like immunofluorescence was both more intense and more widespread than GluR 2/3-like immunolabeling [25].
• The responses of antidromically identified spinothalamic tract (STT) neurons to mechanical and thermal stimuli were compared in anesthetized normal and neuropathic monkeys before and after administration of a GluR5 kainate receptor antagonist (LY382884) into the spinal cord dorsal horn through a microdialysis fiber [26].

References