Hormones and neurotransmitters mobilize Ca 2+ from the endoplasmic reticulum via inositol trisphosphate (IP 3) receptors, but how a single target cell encodes different extracellular signals to generate specific cytosolic Ca 2+ responses is unknown. In pancreatic acinar cells, acetylcholine evokes local Ca 2+ spiking in the apical granular pole, whereas cholecystokinin elicits a mixture of local and global cytosolic Ca 2+ signals. We show that IP 3, cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) evoke cytosolic Ca 2+ spiking by activating common oscillator units composed of IP 3 and ryanodine receptors. Acetylcholine activation of these common oscillator units is triggered via IP 3 receptors, whereas cholecystokinin responses are triggered via a different but converging pathway with NAADP and cyclic ADP-ribose receptors. Cholecystokinin potentiates the response to acetylcholine, making it global rather than local, an effect mediated specifically by cyclic ADP-ribose receptors. In the apical pole there is a common early activation site for Ca 2+ release, indicating that the three types of Ca 2+ release channels are clustered together and that the appropriate receptors are selected at the earliest step of signal generation.