Transformation of local Ca(2+) spikes to global Ca(2+) transients: the combinatorial roles of multiple Ca(2+) releasing messengers

In pancreatic acinar cells, low, threshold concentrations of acetylcholine (ACh) or cholecystokinin (CCK) induce repetitive local cytosolic Ca(2+) spikes in the apical pole, while higher concentrations elicit global signals. We have investigated the process that transforms local Ca(2+) spikes to global Ca(2+) transients, focusing on the interactions of multiple intracellular messengers. ACh-elicited local Ca(2+) spikes were transformed into a global sustained Ca(2+) response by cyclic ADP-ribose (cADPR) or nicotinic acid adenine dinucleotide phosphate (NAADP), whereas inositol 1,4,5-trisphosphate (IP(3)) had a much weaker effect. In contrast, the response elicited by a low CCK concentration was strongly potentiated by IP(3), whereas cADPR and NAADP had little effect. Experiments with messenger mixtures revealed a local interaction between IP(3) and NAADP and a stronger global potentiating interaction between cADPR and NAADP. NAADP strongly amplified the local Ca(2+) release evoked by a cADPR/IP(3) mixture eliciting a vigorous global Ca(2+) response. Different combinations of Ca(2+) releasing messengers can shape the spatio-temporal patterns of cytosolic Ca(2+) signals. NAADP and cADPR are emerging as key messengers in the globalization of Ca(2+) signals.