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Treatment of human epithelial kidney (HEK293) cells with low concentrations of the muscarinic agonist methacholine results in the activation of complex and repetitive cycling of intracellular calcium (Ca(2+)(i)), known as Ca(2+)(i) oscillations. These oscillations occur with a frequency that depends on the concentration of methacholine, whereas the magnitude of the Ca(2+)(i) spikes does not. The oscillations do not persist in the absence of extracellular Ca(2+), leading to the conclusion that entry of Ca(2+) across the plasma membrane plays a significant role in either their initiation or maintenance. However, treatment of cells with high concentrations of GdCl(3), a condition which limits the flux of calcium ions across the plasma membrane in both directions, allows sustained Ca(2+)(i) oscillations to occur. This suggests that the mechanisms that both initiate and regenerate Ca(2+)(i) oscillations are intrinsic to the intracellular milieu and do not require entry of extracellular Ca(2+). This would additionally suggest that, under normal conditions, the role of calcium entry is to sustain Ca(2+)(i) oscillations. By utilizing relatively specific pharmacological manoeuvres we provide evidence that the Ca(2+) entry that supports Ca(2+) oscillations occurs through the store-operated or capacitative calcium entry pathway. However, by artificial introduction of a non-store-operated pathway into the cells (TRPC3 channels), we find that other Ca(2+) entry mechanisms can influence oscillation frequency in addition to the store-operated channels.
Bird et al. (2004) studied this question.