Coordination of agonist-induced Ca2+-signalling patterns by NAADP in pancreatic acinar cells

Many hormones and neurotransmitters evoke Ca2+ release from intracellular stores, often triggering agonist-specific signatures of intracellular Ca2+ concentration(1-5), Inositol trisphosphate (InsP(3))(1) and cyclic adenosine 5 '-diphosphate-ribose (cADPR)(6,7) are established Ca2+-mobilizing messengers that activate Ca2+ release through intracellular InsP(3) and ryanodine receptors, respectively(8-10). However, in pancreatic acinar cells, neither mess enger can explain the complex pattern of Ca2+ signals triggered by the secretory hormone cholecystokinin (CCK). We show here that the Ca2+-mobilizing molecule nicotinic acid adenine dinucleotide phosphate (NAADP)(7,11-13), and endogenous metabolite of P-NADP, triggers a Ca2+ response that varies from short-lasting Ca2+ spikes to a complex mixture of short-lasting (1-2s) and long-lasting (0.2-1 min) Ca2+ spikes. Cells were significantly more sensitive to NAADP than to either cADPR or InsP(3), whereas higher conEeni trations of NAADP selectively inactivated CCK-evoked Ca2+ signals in pancreatic acinar cells, indicating that NAADP may function as an intracellular messenger in mammalian cells.