Okadaic acid uncouples calcium entry from depletion of intracellular stores.

The mechanism by which the depletion of intracellular Ca2+ stores stimulates Ca2+ influx is poorly understood. However, the coupling of depletion to influx is broken during mitosis [Preston, S.F. et. al., (1991) Cell Regul., 2, 915-925]. Thus, in interphase HeLa cells, activation of the histamine H1 receptor, or incubation with thapsigargin, which inhibits the Ca(2+)-ATPase of storage vesicles and depletes Ca2+ stores, strongly stimulate Ca2+ influx. In mitotic cells, however, neither histamine nor thapsigargin stimulate Ca2+ influx. Since it has been found that okadaic acid treatment of interphase cells induces a mitotic-like state with respect to a number of other membrane processes, we have asked if okadaic acid might also uncouple Ca2+ depletion from stimulated influx. We show that okadaic acid specifically does suppress this coupling: thapsigargin and histamine deplete stores in control and okadaic-acid-treated HeLa cells, but after treatment with okadaic acid, stimulation of Ca2+ influx is barely detectable. This suggests that a protein phosphorylation/dephosphorylation event controls the coupling of Ca2+ stores to influx, and that there may be a physiological mechanism for control of the Ca2+ response to hormonal signals at the level of coupling.