Calyculin A, okadaic acid and W-7 interfere with a distal step in pancreatic acinar signal transduction.

The effects of the serine/threonine phosphatase inhibitors calyculin A, okadaic acid and the calmodulin antagonist W-7 on amylase secretion were studied in pancreatic acini. Calyculin A and okadaic acid dose-dependently inhibited amylase secretion to basal levels when stimulated with the intracellularly acting secretagogues thapsigargin, 8-br-cAMP or PMA. W-7 dose-dependently inhibited thapsigargin- or 8-br-cAMP-induced amylase secretion. In combination, thapsigargin, 8-br-cAMP and PMA induced amylase secretion comparable to the stimulation by cholecystokinin. Their effect was significantly inhibited by calyculin A, okadaic acid or W-7. These data imply that type 1- and 2b-phosphatases and calmodulin play a key role in the stimulation of exocrine pancreatic secretion at a distal step of both the Ca2+/IP3- and cAMP-mediated signal-transduction pathways.