TRANSIENT CALCIUM RELEASE INDUCED BY SUCCESSIVE INCREMENTS OF INOSITOL 1,4,5-TRISPHOSPHATE

Many hormonal, neurotransmitter, and sensory stimuli trigger the formation of inositol 1,4,5-trisphosphate, which in turn releases calcium from intracellular stores. We report here that inositol 1,4,5-trisphosphate-induced calcium release from saponin-permeabilized rat basophillic leukemia cells at 37°C is markedly biphasic, in contrast with nearly monophasic release kinetics at 11°C. Hepatoma, PC-12 neuronal cells, and several other cell types exhibit similar biphasic release at 37°C. The biphasic kinetics are not due to degradation of inositol 1,4,5-trisphosphate or to increased Ca2+-ATPase pump activity. Biphasic calcium release was also seen when ATP was quenched to <0.4 μM by adding hexokinase and glucose, suggesting that phosphorylation is not involved. External calcium (100 nM-600 mM) range had little influence on the biphasic kinetics. Rapid-mixing experiments revealed that rapid efflux of calcium is followed in ≃ 0.5 s by a 30-fold slower efflux. Most striking, successive additions of the same amount of inositol 1,4,5-trisphosphate induced short bursts of calcium release of similar size. This retention of responsiveness, which we term increment detection, may be a distinct mode of signal transduction. Like inactivation and adaption, increment detection gives rise to transient responses to sustained stimuli. Systems exhibiting inactivation, adaption, and increment detection differ in their responsiveness (none, partial, and full, respectively) to stepwise increases in stimulus intensity. Increment detection could be advantageous in generating receptor-triggered calcium oscillations.