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

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Abstract
Hormones and neurotransmitters mobilize Ca2+ from the endoplasmic reticulum via inositol trisphosphate (IP3) receptors, but how a single target cell encodes different extracellular signals to generate specific cytosolic Ca2+ responses is unknown. In pancreatic acinar cells, acetylcholine evokes local Ca2+ spiking in the apical granular pole, whereas cholecystokinin elicits a mixture of local and global cytosolic Ca2+ signals. We show that IP3, cyclic 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 oscillator units is triggered via IP3 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 Ca2+ release, indicating that the three types of Ca2+ release channels are clustered together and that the appropriate receptors are selected at the earliest step of signal generation.