Elucidation of the ryanodine-sensitive Ca2+ release mechanism of rat pancreatic acinar cells:: modulation by cyclic ADP-ribose and FK506

The effects of cyclic ADP-ribose (cADPR) and the immunosuppressant drug FK506 on microsomal Ca2+ release through a ryanodine-sensitive mechanism were investigated in rat pancreatic acinar cells. After a steady state of 45 Ca2+ uptake into the microsomal vesicles, ryanodine or caffeine was added. Preincubation of the vesicles with cADPR (0.5 muM) shifted the dose-response curve of ryanodine- or caffeine-induced Ca-45(2+) release from the vesicles to the left. Preincubation with cADPR shifted the dose-response curve of the FK506-induced Ca-45(2+) release upward. Preincubation with FK506 (3 muM) shifted the dose-response curve of the ryanodine- or caffeine-induced Ca-45(2+) release to the left by the same extent as that in the case of cADPR. FK506 shifted the dose-response curve of the cADPR-induced Ca-45(2+) release upward. The presence of both cADPR and FK506 enhanced the ryanodine (30 muM)- or caffeine (10 mM)-induced Ca-45(2+) release by the same extent as that in the case of cADPR alone or FK506 alone. These results indicate that cADPR and FK506 modulate the ryanodine-sensitive Ca2+ release mechanism of rat pancreatic acinar cells by increasing the ryanodine or caffeine sensitivity to the mechanism. In addition, there is a possibility that the mechanisms of modulation by cADPR and FK506 are the same. (C) 2004 Elsevier B.V. All rights reserved.