The pancreatic acinar cell has several phenotypic responses to cAMP agonists. At physiologic concentrations of the muscarinic agonist carbachol (1 µM) or the cholecystokinin (CCK) analog caerulein (100 pM), ligands that increase cytosolic Ca²⁺, cAMP acts synergistically to enhance secretion. Supraphysiologic concentrations of carbachol (1 mM) or caerulein (100 nM) suppress secretion and cause intracellular zymogen activation; cAMP enhances both zymogen activation and reverses the suppression of secretion. In addition to stimulating cAMP-dependent protein kinase (PKA), recent studies using cAMP analogs that lack a PKA response have shown that cAMP can also act through the cAMP-binding protein, Epac (Exchange protein activated directly by cyclic AMP). The roles of PKA and Epac in cAMP responses were examined in isolated pancreatic acini. The activation of both cAMP-dependent pathways or the selective activation of Epac was found to enhance amylase secretion induced by physiologic and supraphysiologic concentrations of the muscarinic agonist, carbachol. Similarly, activation of both PKA or the specific activation of Epac enhanced carbachol-induced activation of trypsinogen and chymotrypsinogen. Disorganization of the apical actin cytoskeleton has been linked to the decreased secretion observed with supraphysiologic concentrations of carbachol and caerulein. Although stimulation of PKA and Epac, or Epac alone could largely overcome the decreased secretion observed with either supraphysiologic carbachol or caerulein, stimulation of cAMP pathways did not reduce the disorganization of the apical cytoskeleton. These studies demonstrate that PKA and Epac pathways are coupled to both secretion and zymogen activation in the pancreatic acinar cell.