Bile Acids Induce Ca super(2+) Release from Both the Endoplasmic Reticulum and Acidic Intracellular Calcium Stores through Activation of Inositol Trisphosphate Receptors and Ryanodine Receptors

Gallstones can cause acute pancreatitis, an often fatal disease in which the pancreas digests itself. This is probably because of biliary reflux into the pancreatic duct and subsequent bile acid action on the acinar cells. Because Ca super(2+) toxicity is important for the cellular damage in pancreatitis, we have studied the mechanisms by which the bile acid taurolithocholic acid 3-sulfate (TLC-S) liberates Ca super(2+). Using two-photon plasma membrane permeabilization and measurement of [Ca super(2+)] inside intracellular stores at the cell base (dominated by ER) and near the apex (dominated by secretory granules), we have characterized the Ca super(2+) release pathways. Inhibition of inositol trisphosphate receptors (IP sub(3)Rs), by caffeine and 2-APB, reduced Ca super(2+) release from both the ER and an acidic pool in the granular area. Inhibition of ryanodine receptors (RyRs) by ruthenium red (RR) also reduced TLC-S induced liberation from both stores. Combined inhibition of IP sub(3)Rs and RyRs abolished Ca super(2+) release. RyR activation depends on receptors for nicotinic acid adenine dinucleotide phosphate (NAADP), because inactivation by a high NAADP concentration inhibited release from both stores, whereas a cyclic ADPR-ribose antagonist had no effect. Bile acid-elicited intracellular Ca super(2+) liberation from both the ER and the apical acidic stores depends on both RyRs and IP sub(3)Rs.