Disease relevance of Grik1

• This assumption is corroborated by the observation (Mackler and Eberwine, 1993) that GluR5 mRNA is completely unedited in neurons of the hippocampal CA1-subfield, a region most vulnerable to transient cerebral ischemia [1].
• The ischemia-induced upregulation of GluR5 mRNA editing observed in the striatum may be indicative of a higher sensitivity to transient ischemia of neurons that exhibit a large fraction of unedited GluR5 mRNA [1].
• In addition, 2S,4R-4MG fully desensitized native kainate receptors (of the GluR5 subtype) in dorsal root ganglion neurons with an IC50 of 11 nM, compared to 3.4 microM for glutamate [2].
• 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 [3].
• In young rats in vivo, the GluR5 selective agonist ATPA was antinociceptive and antihyperalgesic in a model of inflammatory hyperalgesia (ED(50) approximately 4.6 and approximately 5.2 mg/kg, respectively), whereas the GluR5/GluR6 agonist SYM2081 was only antihyperalgesic [4].

Psychiatry related information on Grik1

• RESULTS: AMPA, kainic acid and the GluR5 selective agonist ATPA, all suppressed spontaneous locomotor activity (SLA) in rats at doses of 1.0, 5.0 and 20 mg/kg resp. All three agonists achieve micromolar concentrations measured in whole brain after dosing with 10 mg/kg SC [5].
• Earlier work has shown that systemic administration of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 (mGlu5) antagonist, is able to disrupt classical conditioning in CTA [6].

High impact information on Grik1

• Sequence homology between complementary DNA clones encoding non-NMDA glutamate receptor subunits reveals at least two subunit classes: the GluR1 to GluR4 class and the GluR5 class [7].
• The induction of this form of synaptic plasticity is eliminated by selective antagonists of GluR5 kainate receptors and can be mimicked by the GluR5 agonist ATPA [8].
• We studied the modulation of GABAergic inhibition by glutamate and kainate acting on GluR5-containing kainate receptors in the CA1 hippocampal region [9].
• GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells [9].
• These effects are prevented by the GluR5 antagonist LY 293558 [9].

Chemical compound and disease context of Grik1

• Results indicate that mRNA editing is regulated differently in each of the glutamate receptor subunits GluR2, GluR5, and GluR6 after transient cerebral ischemia [1].
• Expression of metabotropic glutamate receptor 5 is increased in astrocytes after kainate-induced epileptic seizures [10].
• Dysfunction of the cortico-basal ganglia-cortical loop in a rat model of early parkinsonism is reversed by metabotropic glutamate receptor 5 antagonism [11].
• Here we report that the NMDA receptor antagonist D-AP5 (50 microM), the L-type calcium channel antagonist nifedipine (30 microM) and the metabotropic glutamate receptor 5 antagonist MPEP (10 microM) prevented L-LTP induction when each antagonist was separately applied at saturating concentrations before and during repeated tetanus [12].

Biological context of Grik1

• Using a mammalian expression system we demonstrate here that homomeric GluR-5 receptors exhibit properties of a high affinity domoate (KD approximately 2 nM) and kainate (KD approximately 70 nM) binding site [13].
• 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 [14].
• FISH was used to localize the transgene insertion to chromosome 11q11-q12, proximal to Grik1 and near Ncam2 [15].
• During embryogenesis, GluR5 transcripts are detected in areas of neuronal differentiation and synapse formation [16].
• RNA was converted by reverse transcription into cDNA, which was used as a template for subunit-specific polymerase chain reaction (PCR) to amplify a product across the edited base A (A edited to I in the second transmembrane-spanning regions of GluR2, GluR5, and GluR6) [1].

Anatomical context of Grik1

• GluR-5 transcripts are in the cingulate and piriform cortex, the subiculum, lateral septal nuclei, anteroventral thalamus, suprachiasmatic nucleus, the tegmental nuclei, pontine nuclei, and Purkinje cells [17].
• Glutamate receptor subunits GluR5 and KA-2 are coexpressed in rat trigeminal ganglion neurons [18].
• In the present study, we demonstrate immunocytochemically that the majority of neurons in rat cerebral cortex coexpress members of all three groups of glutamate receptor subunits, Glu R2/3, Glu R5/6/7, and NMDA R1 [19].
• We studied the messenger ribonucleic acid (mRNA) and protein expression of GluR5, GluR6, and GluR7 in rat hippocampus 72 h, 90 days, and 180 days after KA-induced SE [14].
• Single-cell RT-PCR showed relative abundances of mRNAs for the KA receptors, GluR5, GluR6 and GluR7, of 12, 33 and 54% for cortical neurones and 38, 10 and 54% for spinal cord neurones, respectively [20].

Associations of Grik1 with chemical compounds

• The non-NMDA family of glutamate receptors comprises a growing number of structurally related subunits (GluR-A to -D or -1 to -4; GluR-5, -6; KA-1) [13].
• The results show that the KA2-containing GnRH neurons also contain GluR5 receptor subunit mRNA and protein, and that these GnRH neurons are c-Fos positive during the steroid-induced LH surge [21].
• The phosphono amino acid, (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl+ ++]propio nic acid (ATPO), is a structural hybrid between the NMDA antagonist (RS)-2-amino-7-phosphonoheptanoic acid (AP7) and the AMPA and GluR5 agonist, (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA) [22].
• The GluR5 protein forms homomeric ion channels in Xenopus oocytes that are weakly responsive to L-glutamate [16].
• The GluR-5 gene shows peaks of expression around the period of birth in the sensory cortex (layers II, III, and IV), in CA1 hippocampal interneurons in the stratum oriens, in the septum, and in the thalamus [23].

Regulatory relationships of Grik1

• 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 [24].
• Metabotropic glutamate receptor 5-induced phosphorylation of extracellular signal-regulated kinase in astrocytes depends on transactivation of the epidermal growth factor receptor [25].

Other interactions of Grik1

• Our data suggest that the heteromeric GluR5/KA2 combination actually occurs in TG neurons and give a clue as to the subunit composition of native kainate receptor channels [18].
• Lamina I contained occasional cells expressing the GluR-5 gene, whereas GluR-7 mRNA was present in scattered cells in all superficial laminae [26].
• Postsynaptic densities of the giant mossy fiber-UBC synapses were GluR2/3, GluR5/6/7, and NR1 immunoreactive [27].
• Within the mesolimbic pathway, reductions were observed in NR1 and GluR5 immunoreactivity in the VTA although no significant alterations were observed in any iGluR subunits in the NAc [28].
• In contrast to recombinantly expressed GluR-A to -D channels, currents elicited at GluR-5 receptor desensitize channels to all agonists [13].

Analytical, diagnostic and therapeutic context of Grik1

• In the present study, we analyzed the distribution of GluR5 subunit protein in the rat hypothalamus with immunohistochemistry [29].
• Polymerase chain reaction studies showed that the glutamate receptor subunits GluR1-4 and GluR6 were all expressed in these cultures, but GluR5 was absent [30].
• The expression of the five known genes encoding kainate receptor subunits (GluR-5, -6, -7, KA-1, and KA-2) was studied by in situ hybridization during pre- and postnatal development of the rat brain [23].
• KA receptors, e.g. GluR5 and GluR6 have been characterized by molecular cloning [3].
• Northern blot analysis of mRNA for dorsal root ganglia revealed a predominant expression of GluR5, indicating that modulation of desensitization by concanavalin A but not cyclothiazide in sensory neurons accurately predicts subunit expression for native glutamate receptors [31].

References