Intercellular calcium waves in rat pancreatic acini: mechanism of transmission.

Digital-imaging microfluorimetry, together with microinjection of marker/messenger molecules, was utilized to investigate intercellular Ca2+ signaling in rat pancreatic acinar cells. Stimulation of acini with low concentrations of secretagogues [< 100 pM cholecystokinin (CCK), < 1 microM carbachol (CCh)] resulted in asynchronous but coordinated increases in Ca2+ that appeared to pass in a "wavelike" fashion between cells. In contrast, at higher supermaximal concentrations of agonists (> 300 pM CCK, > 1 microM CCh), which induce a large "peak-and-plateau" intracellular Ca2+ signal, all cells in the acinus appeared to increase Ca2+ concentration ([Ca2+]) in synchrony. Microinjection of lissarhodamine, a marker of gap-junctional permeability, into cells previously loaded with fura 2 allowed the simultaneous measurement of gap-junctional coupling and [Ca2+]. Stimulation with supermaximal concentrations of agonists resulted in the attenuation of junctional permeability, whereas, during stimulation with physiological concentrations of agonist, junctional communication remained operable. Injection of inositol 1,4,5-triphosphate [Ins(1,4,5)P3] into one cell of an acinar cluster resulted in the generation of a Ca2+ signal in the injected cell and adjacent cells. In contrast, injection of CaCl2 itself did not result in propagation of the signal. When CaCl2 was injected into cells that had been previously stimulated with a threshold concentration of CCK, propagation of a signal was observed between cells. On the basis of these data, a model is proposed in which Ca2+ acts as coagonist with Ins(1,4,5)P3 to potentiate the Ca(2+)-releasing action of Ins(1,4,5)P3 and, by diffusion of the two molecules through gap junctions, underlies intercellular signaling in acinar cells. Gap-junctional communication may be an important factor in amplifying a threshold signal produced in one cell throughout the acinus, resulting in enhanced stimulated secretion in acinar preparations compared with preparations of isolated cells.