We studied cAMP-mediated exocytosis in rat pancreatic acinar cells. We monitored changes in the membrane capacitance ((C), which reflects the granule fusion/retrieval process, with whole-cell patch-clamp capacitance measurement. The rise in cellular cAMP, caused indirectly by receptor activation by vasoactive intestinal polypeptide or directly by dibutyryl cyclic AMP, was able to induce an increase in (C independently of cellular Ca²⁺. Using the latter stimulation, we estimated the magnitude of the response to internal GTP%S [guanosine 5'-(%-thio)trisphosphate] and/or GDP#S [guanosine 5'-(#-thio)diphosphate]. The internal GTP%S and GDP#S amplified and depressed the response, respectively. Thus, the cellular cAMP alone can trigger granule insertion independently of cellular Ca²⁺ and it can be controlled by cellular GTP-binding proteins, presumably those belonging to the Rab family.