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Kainate Receptor Subunits (kainate + receptor_subunit)

Distribution by Scientific Domains
Life Sciences75%

Selected Abstracts

Subunit-specific desensitization of heteromeric kainate receptors

THE JOURNAL OF PHYSIOLOGY, Issue 4 2010
David D. Mott
Kainate receptor subunits can form functional channels as homomers of GluK1, GluK2 or GluK3, or as heteromeric combinations with each other or incorporating GluK4 or GluK5 subunits. However, GluK4 and GluK5 cannot form functional channels by themselves. Incorporation of GluK4 or GluK5 into a heteromeric complex increases glutamate apparent affinity and also enables receptor activation by the agonist AMPA. Utilizing two-electrode voltage clamp of Xenopus oocytes injected with cRNA encoding kainate receptor subunits, we have observed that heteromeric channels composed of GluK2/GluK4 and GluK2/GluK5 have steady state concentration,response curves that were bell-shaped in response to either glutamate or AMPA. By contrast, homomeric GluK2 channels exhibited a monophasic steady state concentration,response curve that simply plateaued at high glutamate concentrations. By fitting several specific Markov models to GluK2/GluK4 heteromeric and GluK2 homomeric concentration,response data, we have determined that: (a) two strikingly different agonist binding affinities exist; (b) the high-affinity binding site leads to channel opening; and (c) the low-affinity agonist binding site leads to strong desensitization after agonist binding. Model parameters also approximate the onset and recovery kinetics of desensitization observed for macroscopic currents measured from HEK-293 cells expressing GluK2 and GluK4 subunits. The GluK2(E738D) mutation lowers the steady state apparent affinity for glutamate by 9000-fold in comparison to GluK2 homomeric wildtype receptors. When this mutant subunit was expressed with GluK4, the rising phase of the glutamate steady state concentration,response curve overlapped with the wildtype curve, whereas the declining phase was right-shifted toward lower affinity. Taken together, these data are consistent with a scheme whereby high-affinity agonist binding to a non-desensitizing GluK4 subunit opens the heteromeric channel, whereas low-affinity agonist binding to GluK2 desensitizes the whole channel complex. [source]

Association of Markers in the 3, Region of the GluR5 Kainate Receptor Subunit Gene to Alcohol Dependence

ALCOHOLISM, Issue 5 2009
Henry R. Kranzler
Background:, Glutamate neurotransmission plays an important role in a variety of alcohol-related phenomena, including alcohol self-administration by both animals and humans. Because the risk for alcohol dependence (AD) is genetically influenced, genes encoding glutamate receptors are candidates to contribute to the risk for AD. We examined the role of variation in the 3, region of GRIK1, the gene that encodes the GluR5 receptor subunit of the kainic acid glutamate receptor, on risk for AD. We focused specifically on this gene because topiramate, a glutamate modulator that binds to the GluR5 subunit, has shown robust efficacy in the treatment of AD. Methods:, We genotyped 7 single nucleotide polymorphisms (SNPs) in the 3,-half of GRIK1, which includes 3 differentially spliced exons, in a sample of EA control subjects (n = 507) and subjects with AD (n = 1,057). Results:, We found nominally significant evidence of association to AD for 3 SNPs (rs2832407 in intron 9, rs2186305 in intron 17, and rs2832387 in the 3,UTR). Empirical p -value estimation revealed that only rs2832407 was significantly associated to phenotype (p = 0.043). Discussion:, These findings provide support for the hypothesis that variation in the 3, portion of the gene encoding the GluR5 kainate receptor subunit contributes to the risk for AD. Further research is needed to ascertain whether this SNP is itself functional or whether the association reflects linkage disequilibrium with functional variation elsewhere in the gene and whether this SNP moderates topiramate's effects in the treatment of AD. [source]

Role of kainate receptor activation and desensitization on the [Ca2+]i changes in cultured rat hippocampal neurons

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2001
Ana P. Silva
Abstract We investigated the role of kainate (KA) receptor activation and desensitization in inducing the increase in the intracellular free Ca2+ concentration ([Ca2+]i) in individual cultured rat hippocampal neurons. 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. The effect of LY303070, an ,-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor antagonist, on the alterations in the [Ca2+]i caused by kainate showed cell-to-cell variability. The [Ca2+]i increase caused by kainate was mostly mediated by the activation of AMPA receptors because LY303070 inhibited the response to kainate in a high percentage of neurons. The response to kainate was potentiated by concanavalin A (Con A), which inhibits kainate receptor desensitization, in 82.1% of the neurons, and this potentiation was not reversed by LY303070 in about 38% of the neurons. Also, upon stimulation of the cells with 4-methylglutamate (MGA), a selective kainate receptor agonist, in the presence of Con A, it was possible to observe [Ca2+]i changes induced by kainate receptor activation, because LY303070 did not inhibit the response in all neurons analyzed. In toxicity studies, cultured rat hippocampal neurons were exposed to the drugs for 30 min, and the cell viability was evaluated at 24 hr using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The selective activation of kainate receptors with MGA, in the presence of Con A, induced a toxic effect, which was not prevented by LY303070, revealing a contribution of a small subpopulation of neurons expressing kainate receptors that independently mediate cytotoxicity. Taken together, these results indicate that cultured hippocampal neurons express not only AMPA receptors, but also kainate receptors, which can modulate the [Ca2+]i and toxicity. J. Neurosci. Res. 65:378,386, 2001. © 2001 Wiley-Liss, Inc. [source]

Subunit-specific desensitization of heteromeric kainate receptors

THE JOURNAL OF PHYSIOLOGY, Issue 4 2010
David D. Mott
Kainate receptor subunits can form functional channels as homomers of GluK1, GluK2 or GluK3, or as heteromeric combinations with each other or incorporating GluK4 or GluK5 subunits. However, GluK4 and GluK5 cannot form functional channels by themselves. Incorporation of GluK4 or GluK5 into a heteromeric complex increases glutamate apparent affinity and also enables receptor activation by the agonist AMPA. Utilizing two-electrode voltage clamp of Xenopus oocytes injected with cRNA encoding kainate receptor subunits, we have observed that heteromeric channels composed of GluK2/GluK4 and GluK2/GluK5 have steady state concentration,response curves that were bell-shaped in response to either glutamate or AMPA. By contrast, homomeric GluK2 channels exhibited a monophasic steady state concentration,response curve that simply plateaued at high glutamate concentrations. By fitting several specific Markov models to GluK2/GluK4 heteromeric and GluK2 homomeric concentration,response data, we have determined that: (a) two strikingly different agonist binding affinities exist; (b) the high-affinity binding site leads to channel opening; and (c) the low-affinity agonist binding site leads to strong desensitization after agonist binding. Model parameters also approximate the onset and recovery kinetics of desensitization observed for macroscopic currents measured from HEK-293 cells expressing GluK2 and GluK4 subunits. The GluK2(E738D) mutation lowers the steady state apparent affinity for glutamate by 9000-fold in comparison to GluK2 homomeric wildtype receptors. When this mutant subunit was expressed with GluK4, the rising phase of the glutamate steady state concentration,response curve overlapped with the wildtype curve, whereas the declining phase was right-shifted toward lower affinity. Taken together, these data are consistent with a scheme whereby high-affinity agonist binding to a non-desensitizing GluK4 subunit opens the heteromeric channel, whereas low-affinity agonist binding to GluK2 desensitizes the whole channel complex. [source]