Effects of epidermal growth factor and calcium omission on cholecystokinin-stimulated Cl− conductance in rat pancreatic zymogen granules

Abstract Evidence suggests that cholecystokinin-octapeptide (CCK-8)-induced activation of a Cl − conductance in the membrane of zymogen granules (ZG) is closely related to pancreatic enzyme secretion [1,2,3]. Following stimulation of isolated pancreatic acinar cells with increasing concentrations of CCK-8, the Cl − conductance in the ZG from these acini increased, reached a maximum of 40±7 % above basal Cl − conductance at 10 −12 M CCK-8, and then decreased at CCK-8 concentrations higher than 10 −9 M to a level comparable to the basal Cl − conductance. We had interpreted the inhibitory action of high CCK-8 concentrations to be due to the generation of high concentrations of diacylglycerol and/or its metabolites by an “overstimulation” of phospholipase C at supramaximal CCK-8 concentrations [1]. We now show that EGF abolishes the downstroke of the dose response curve for CCK-8-induced ZG Cl − conductance and shifts the stimulatory response to higher CCK-8 concentrations. Similarly in a nominally “Ca 2+ -free buffer” (free [Ca 2+ ] ∼0.2 nM), stimulated Cl − conductance at 10 −12 M CCK-8 is nearly abolished and the decreased Cl − conductance at 10 −8 M CCK-8 is increased to the level of maximal stimulation at 1o −12 M CCK-8. We conclude that both EGF and low [Ca 2+ ] affect CCK-8-induced ZG Cl − conductance by decreasing phospholipase C activity.