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-de pendently 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-indu ced amylase secretion. In combination, thapsigargin, 8-br-cAMP and PMA induced amy]ase secretion comparable to the stimulation by cholecysto kinin. Their effect was significantly inhibited by calyculin A, okadai c acid or W-7. These data imply that type 1- and 2b-phosphatases and c almodulin play a key role in the stimulation of exocrine pancreatic se cretion at a distal step of bath the Ca2+/IP3- and cAMP-mediated signa l-transduction pathways. (C) 1994 Academic Press, Inc.