Agonist-dependent phosphorylation of the inositol 1,4,5-trisphosphate receptor - A possible mechanism for agonist-specific calcium oscillations in pancreatic acinar cells

The properties of inositol 1,4,5 -trisphosphate (IP3,)-dependent intracellu lar calcium oscillations in pancreatic acinar cells depend crucially on the agonist used to stimulate them. Acetylcholine or carbachol (CCh) cause hig h-frequency (10-12-s period) calcium oscillations that are superimposed on a raised baseline, while cholecystokinin (CCK) causes long-period (>100s pe riod) baseline spiking. We show that physiological concentrations of CCK in duce rapid phosphorylation of the IP3 receptor, which is not true of physio logical concentrations of CCh. Based on this and other experimental data, w e construct a mathematical model of agonist-specific intracellular calcium oscillations in pancreatic acinar cells. Model simulations agree with previ ous experimental work on the rates of activation and inactivation of the IF , receptor by calcium (DuFour, J.-F., I.M. Arias, and T.J. Turner. 1997. J. Biol. Chem. 272:2675-2681), and reproduce both short-period, raised baseli ne oscillations, and long-period baseline spiking. The steady state open pr obability curve of the model IF, receptor is an increasing function of calc ium concentration, as found for type-III IF, receptors by Hagar et al. (Hag ar, R.E., A.D. Burgstahler, M.H. Nathanson, and B.E. Ehrlich. 1998. Nature. 396:81-84). We use the model to predict the effect of the removal of exter nal calcium, and this prediction is confirmed experimentally. We also predi ct that, for type-III IP3 receptors, the steady state open probability curv e will shift to lower calcium concentrations as the background IP3 concentr ation increases. We conclude that the differences between CCh- and CCK-indu ced calcium oscillations in pancreatic acinar cells can be explained by two principal mechanisms: (a) CCK causes more phosphorylation of the IP3 recep tor than does CCh, and the phosphorylated receptor cannot pass calcium curr ent; and (b) the rate of calcium ATPase pumping and the rate of calcium inf lux from the outside the cell are greater in the presence of CCh than in th e presence of CCK.