Kinetic Control of Multiple Forms of Ca²⁺ Spikes by Inositol Trisphosphate in Pancreatic Acinar Cells

The mechanisms of agonist-induced Ca²⁺ spikes have been investigated using a caged inositol 1,4,5-trisphosphate (IP₃) and a low-affinity Ca²⁺ indicator, BTC, in pancreatic acinar cells. Rapid photolysis of caged IP₃ was able to reproduce acetylcholine (ACh)-induced three forms of Ca²⁺ spikes: local Ca²⁺ spikes and submicromolar (<1 μM) and micromolar (1–15 μM) global Ca²⁺ spikes (Ca²⁺ waves). These observations indicate that subcellular gradients of IP₃ sensitivity underlie all forms of ACh-induced Ca²⁺ spikes, and that the amplitude and extent of Ca²⁺ spikes are determined by the concentration of IP₃. IP₃-induced local Ca²⁺ spikes exhibited similar time courses to those generated by ACh, supporting a role for Ca²⁺-induced Ca²⁺ release in local Ca²⁺ spikes. In contrast, IP₃- induced global Ca²⁺ spikes were consistently faster than those evoked with ACh at all concentrations of IP₃ and ACh, suggesting that production of IP₃ via phospholipase C was slow and limited the spread of the Ca²⁺ spikes. Indeed, gradual photolysis of caged IP₃ reproduced ACh-induced slow Ca²⁺ spikes. Thus, local and global Ca²⁺ spikes involve distinct mechanisms, and the kinetics of global Ca²⁺ spikes depends on that of IP₃ production particularly in those cells such as acinar cells where heterogeneity in IP₃ sensitivity plays critical role.