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© The Rockefeller University Press, 0022-1295/1999//851/ $5.00
Journal of General Physiology, Volume 113, Number 6, 1999

Article

Agonist-dependent Phosphorylation of the Inositol 1,4,5-Trisphosphate Receptor

A Possible Mechanism for Agonist-specific Calcium Oscillations in Pancreatic Acinar Cells



Andrew P. LeBeau, David I. Yule{ddagger}, Guy E. Groblewski{ddagger}, and James Sneyd§

From the Mathematical Research Branch, National Institutes of Health, Bethesda, Maryland; {ddagger} Department of Physiology and § Department of Mathematics, University of Michigan, Ann Arbor, Michigan 48109-1109

The properties of inositol 1,4,5-trisphosphate (IP3)-dependent intracellular calcium oscillations in pancreatic acinar cells depend crucially on the agonist used to stimulate them. Acetylcholine or carbachol (CCh) cause high-frequency (10–12-s period) calcium oscillations that are superimposed on a raised baseline, while cholecystokinin (CCK) causes long-period (>100-s period) baseline spiking. We show that physiological concentrations of CCK induce rapid phosphorylation of the IP3 receptor, which is not true of physiological concentrations of CCh. Based on this and other experimental data, we construct a mathematical model of agonist-specific intracellular calcium oscillations in pancreatic acinar cells. Model simulations agree with previous experimental work on the rates of activation and inactivation of the IP3 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 baseline oscillations, and long-period baseline spiking. The steady state open probability curve of the model IP3 receptor is an increasing function of calcium concentration, as found for type-III IP3 receptors by Hagar et al. (Hagar, 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 external calcium, and this prediction is confirmed experimentally. We also predict that, for type-III IP3 receptors, the steady state open probability curve will shift to lower calcium concentrations as the background IP3 concentration increases. We conclude that the differences between CCh- and CCK-induced calcium oscillations in pancreatic acinar cells can be explained by two principal mechanisms: (a) CCK causes more phosphorylation of the IP3 receptor than does CCh, and the phosphorylated receptor cannot pass calcium current; and (b) the rate of calcium ATPase pumping and the rate of calcium influx from the outside the cell are greater in the presence of CCh than in the presence of CCK.

Key Words: inositol 1,4,5-trisphosphate receptor • phosphorylation • protein kinase A • mathematical model • calcium oscillations

Address correspondence to Dr. James Sneyd, Department of Mathematics, University of Michigan, 525 E. University Ave., East Hall, Ann Arbor, MI 48109-1109. Fax: 734-763-0937; E-mail: jsneyd{at}math.lsa.umich.edu

Abbreviations: Ach, acetylcholine; CaMK-II, Ca2+-calmodulin kinase II; CCK, cholecystokinin; CPA, cyclopiazonic acid; ER, endoplasmic reticulum; IP3, inositol 1,4,5-trisphosphate; IP3R, IP3 receptor


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