Mechanisms of intracellular Ca2+ mobilization induced by taurochenodeoxycholic acid in rat hepatocytes.

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It is well known that certain bile acids increase cytosolic free Ca2+ concentration ([Ca2+]c) in rat hepatocytes. We studied phospholipase C activation in intact rat hepatocytes and Ca2+ release in digitonin-permeabilized cells to clarify the mechanisms of [Ca2+]c mobilization induced by taurochenodeoxycholic acid (TCDCA). TCDCA (0.1-1mM) increased [Ca2+]c both in cell suspensions and in single hepatocytes. When cells were pretreated with EGTA (2mM), the response became transient but the initial rate of Ca2+ release was not affected, indicating that initial Ca2+ release induced by TCDCA originates from intracellular Ca2+ storage organelles. Inositol trisphosphate (InsP3) transiently accumulated in a dose-dependent manner after the addition of TCDCA. In permeabilized cells, TCDCA also induced Ca2+ release from the InsP3-sensitive Ca2+ pool. These responses were sustained, although the InsP3-induced Ca2+ release was transient. The TCDCA-induced Ca2+ release in permeabilized cells was not affected by pretreatment with heparin, an inhibitor of the InsP3 receptor in the endoplasmic reticulum. These studies identified two pathways by which an increase in [Ca2+]c is induced by TCDCA, namely through activation of phospholipase C, generating the second messenger InsP3, and through direct action on the intracellular Ca2+ storage pool.
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