[Ca(2+)](i) oscillation frequency regulates agonist-stimulated NF-kappaB transcriptional activity.
In nonexcitable cells, stimulation by high agonist concentrations typically produces a biphasic increase in cytosolic Ca(2+) ([Ca(2+)](i)). This response is characterized by a transient initial increase because of intracellular Ca(2+) release followed by a sustained elevation which varies in amplitude depending on the nature of the stimulus. In contrast, low-level stimulation often evokes oscillatory changes in [Ca(2+)](i). The specific information provided by repetitive [Ca(2+)](i) spikes appears to be encoded in the frequency rather than in the amplitude of [Ca(2+)](i) oscillations. The specific, membrane-permeable inositol 1,4, 5-trisphosphate (Ins-1,4,5-P(3)) receptor blocker Xestospongin C (XeC, 2-20 microM) was used to affect [Ca(2+)](i) signaling in human aortic endothelial cells (HAEC) during an established response to low-level (1 microM) histamine stimulation. XeC produced a dose-dependent decrease in the frequency of [Ca(2+)](i) oscillations during histamine stimulation without affecting oscillation amplitude. Histamine stimulated a 14-fold increase in NF-kappaB-chloramphenicol acetyltransferase reporter gene activity that was dose-dependently decreased by XeC. Thus, during low-level agonist stimulation, [Ca(2+)](i) oscillation frequency regulates nuclear transcription in HAEC.
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Department of Medicine, Division of Cardiology, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Deshpande
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Irani
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Ziegelstein
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D001011:Aorta / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000737:chemistry / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D016328:NF-kappa B / Q000235:genetics*; D010080:Oxazoles / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D016328:NF-kappa B; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; C108644:xestospongin A; D006632:Histamine; D015544:Inositol 1,4,5-Trisphosphate; D015500:Chloramphenicol O-Acetyltransferase; D002118:Calcium