Two different but converging messenger pathways to intracellular Ca2+ release: the roles of nicotinic acid adenine dinucleotide phosphate, cyclic ADP-ribose and inositol trisphosphate

Hormones and neurotransmitters mobilize Ca2+ from the endoplasmic reticulum via inositol trisphosphate (IP3) receptors, but how a single target cell e ncodes different extracellular signals to generate specific cyto-solic Ca2 responses is unknown. In pancreatic acinar cells, acetylcholine evokes loc al Ca2+ spiking in the apical granular pole, whereas cholecystokinin elicit s a mixture of local and global cytosolic Ca2+ signals. We show that IP3, c yclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) evoke cytosolic Ca2+ spiking by activating common oscillator units composed of IP3 and ryanodine receptors, Acetylcholine activation of these common o scillator units is triggered via IP3 receptors, whereas cholecystokinin res ponses are triggered via a different but converging pathway with NAADP and cyclic ADP-ribose receptors, Cholecystokinin potentiates the response to ac etylcholine, making it global rather than local, an effect mediated specifi cally by cyclic ADP-ribose receptors. In the apical pole there is a common early activation site for Ca2+ release, indicating that the three types of Ca2+ release channels are clustered together and that the appropriate recep tors are selected at the earliest step of signal generation.