CYCLIC-GMP MODULATES DEPLETION-ACTIVATED CA2-CELLS( ENTRY IN PANCREATIC ACINAR)

In the pancreatic acinar cell, hormonal stimulation causes a rise in t he intracellular free Ca2+ concentration by activating the inositol 1, 4,5-trisphosphate-mediated release of Ca2+ from intracellular stores ( Berridge, M. J., and Irvine, R. F. (1989) Nature 341, 197-205). The re leased Ca2+ is, for the most part, extruded from the cell, necessitati ng a mechanism for Ca2+ entry and reloading of intracellular Ca2+ stor es (Putney, J. W., Jr. (1990) Cell Calcium 11, 611-624; Rink, T. J. (1 990) FEBS Lett. 268, 381-385). However, neither the mechanism of deple tion-activated Ca2+ entry nor the signal that activates it is known. W e report here that a sustained inward current of depletion-activated C a2+ entry can be measured in pancreatic acinar cells using patch-clamp recording methods. Furthermore, the current can be blocked by an inhi bitor of guanylyl cyclase, can be reactivated by 8-bromo-cGMP after in hibition, and can be activated in the absence of Ca2+ depletion by per fusing the cell with cGMP, but not cAMP. Intracellular perfusion with 1,3,4,5-inositol tetrakisphosphate did not activate an inward current, whereas perfusion with 2,4,5-inositol trisphosphate did activate an i nward current. We conclude that cGMP may be an intracellular messenger that regulates depletion-activated Ca2+ entry.