INHIBITION OF INOSITOL TRISPHOSPHATE-INDUCED CALCIUM-RELEASE BY CAFFEINE IS PREVENTED BY ATP

We have investigated the effect of various methylxanthines on the basal and InsP(3)-stimulated unidirectional Ca-45(2+) efflux from permeabilized A7r5 cells under different experimental conditions. We report that caffeine and theophylline inhibit the InsP(3)-induced Ca2+ release, whereas the basal Ca2+ leak remained largely unaffected. The effect on InsP(3)-induced Ca2+ release was specific, since isocaffeine was not effective. The inhibition occurred similarly in the absence or presence of extravesicular Ca2+ and was not associated with a decrease in the [H-3]InsP(3) binding to the receptor. ATP and MgATP (5 mM) prevented the inhibition, suggesting that caffeine may interact with an ATP-binding site on the InsP(3) receptor or some associated protein.