Transformation of local Ca2+ spikes to global Ca2+ transients: the combinatorial roles of multiple Ca2+ releasing messengers

摘要

In pancreatic acinar cells, low, threshold concentrations of acetylcholine (ACh) or cholecystokinin (CCK) induce repetitive local cytosolic Ca²⁺ spikes in the apical pole, while higher concentrations elicit global signals. We have investigated the process that transforms local Ca²⁺ spikes to global Ca²⁺ transients, focusing on the interactions of multiple intracellular messengers. ACh-elicited local Ca²⁺ spikes were transformed into a global sustained Ca²⁺ response by cyclic ADP-ribose (cADPR) or nicotinic acid adenine dinucleotide phosphate (NAADP), whereas inositol 1,4,5-trisphosphate (IP3) had a much weaker effect. In contrast, the response elicited by a low CCK concentration was strongly potentiated by IP3, whereas cADPR and NAADP had little effect. Experiments with messenger mixtures revealed a local interaction between IP3 and NAADP and a stronger global potentiating interaction between cADPR and NAADP. NAADP strongly amplified the local Ca²⁺ release evoked by a cADPR/IP3 mixture eliciting a vigorous global Ca²⁺ response. Different combinations of Ca²⁺ releasing messengers can shape the spatio-temporal patterns of cytosolic Ca²⁺ signals. NAADP and cADPR are emerging as key messengers in the globalization of Ca²⁺ signals.