Change in cytosolic free calcium ion concentration [Ca2+]c, resulting from receptor activation by an appropriate agonist, functions as a cardinal intracellular signaling in the stimulus-secretion coupling in a wide variety of secretory cells including the acini of the pancreas. Ratiometric imaging of [Ca2+]c, dynamics by UV-laser scanning confocal microscopy led us to conclude that in the cholecystokinin (CCK)-8-induced recurrent [Ca2+]c, spiking increases initially in the basolateral margin of the acinus and propagates to the luminal margin. [Ca2+]c, in this initial cell increased rapidly and uniformly to the maximum level. The decrease in [Ca2+]c, in the initial cell coincided with a small increase in [Ca2+]c, in the luminal regions of the bilateral neighboring cells followed by uniform maximal increase in [Ca2+]c, in these neighboring cells. A series of [Ca2+]c, dynamics was repeated to form recurrent Ca2+ spiking. The temporal sequences of [Ca2+]c, dynamics recorded during continuous stimulation with CCK-8 at a physiologic concentration in individual acinar cells forming the acinus were displayed on the identical time scale. The figure indicates that the signaling is not synchronous in cells forming an acinus. From these and other results, we proposed a model in which CCK-8 at a low physiologic concentration binds to highly sensitive CCK receptor interacting with heterotrimeric guanosine 5'-triphosphate-binding proteins of the Gq class, generate Ins 1,4,5-P3, and recurrent [Ca2+]c, spiking. The recurrent Ca2+ spiking maintains a sustained secretory response, recurrent exocytosis of zymogen granules, and concomitant secretion of isotonic NaCl.