[Ca²⁺](i) Oscillation frequency regulates agonist-stimulated NF-κB transcriptional activity

In nonexcitable cells, stimulation by high agonist concentrations typically produces a biphasic increase in cytosolic Ca²⁺ ([Ca²⁺](i)). This response is characterized by a transient initial increase because of intracellular Ca²⁺ 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 [Ca²⁺](i). The specific information provided by repetitive [Ca²⁺](i) spikes appears to be encoded in the frequency rather than in the amplitude of [Ca²⁺](i) oscillations. The specific, membrane-permeable inositol 1,4,5-trisphosphate (Ins-1,4,5-P₃) receptor blocker Xestospongin C (XeC, 2-20 μM) was used to affect [Ca²⁺](i) signaling in human aortic endothelial cells (HAEC) during an established response to low-level (1 μM) histamine stimulation. XeC produced a dose-dependent decrease in the frequency of [Ca²⁺](i) oscillations during histamine stimulation without affecting oscillation amplitude. Histamine stimulated a 14-fold increase in NF-κB-chloramphenicol acetyltransferase reporter gene activity that was dose-dependently decreased by XeC. Thus, during low-level agonist stimulation, [Ca²⁺](i) oscillation frequency regulates nuclear transcription in HAEC.