Localized Ca(2+) uncaging reveals polarized distribution of Ca(2+)-sensitive Ca(2+) release sites: mechanism of unidirectional Ca(2+) waves

Ca(2+)-induced Ca(2+) release (CICR) plays an important role in the generation of cytosolic Ca(2+) signals in many cell types. However, it is inherently difficult to distinguish experimentally between the contributions of messenger-induced Ca(2+) release and CICR. We have directly tested the CICR sensitivity of different regions of intact pancreatic acinar cells using local uncaging of caged Ca(2+). In the apical region, local uncaging of Ca(2+) was able to trigger a CICR wave, which propagated toward the base. CICR could not be triggered in the basal region, despite the known presence of ryanodine receptors. The triggering of CICR from the apical region was inhibited by a pharmacological block of ryanodine or inositol trisphosphate receptors, indicating that global signals require coordinated Ca(2+) release. Subthreshold agonist stimulation increased the probability of triggering CICR by apical uncaging, and uncaging-induced CICR could activate long-lasting Ca(2+) oscillations. However, with subthreshold stimulation, CICR could still not be initiated in the basal region. CICR is the major process responsible for global Ca(2+) transients, and intracellular variations in sensitivity to CICR predetermine the activation pattern of Ca(2+) waves.