Mutual Antagonism of Calcium Entry by Capacitative and Arachidonic Acid-mediated Calcium Entry Pathways

Abstract

In nonexcitable cells, the predominant mechanism for regulated entry of Ca2+ is capacitative calcium entry, whereby depletion of intracellular Ca2+ stores signals the activation of plasma membrane calcium channels. A number of other regulated Ca2+ entry pathways occur in specific cell types, however, and it is not know to what degree the different pathways interact when present in the same cell. In this study, we have examined the interaction between capacitative calcium entry and arachidonic acid-activated calcium entry, which co-exist in HEK293 cells. These two pathways exhibit mutual antagonism. That is, capacitative calcium entry is potently inhibited by arachidonic acid, and arachidonic acid-activated entry is inhibited by the pre-activation of capacitative calcium entry with thapsigargin. In the latter case, the inhibition does not seem to result from a direct action of thapsigargin, inhibition of endoplasmic reticulum Ca2+ pumps, depletion of Ca2+ stores, or entry of Ca2+ through capacitative calcium entry channels. Rather, it seems that a discrete step in the pathway signaling capacitative calcium entry interacts with and inhibits the arachidonic acid pathway. The findings reveal a novel process of mutual antagonism between two distinct calcium entry pathways. This mutual antagonism may provide an important protective mechanism for the cell, guarding against toxic Ca2+ overload.