Regulation of Ca2+ release through inositol 1,4,5-trisphosphate receptors by adenine nucleotides in parotid acinar cells

Park HS, Betzenhauser MJ, Zhang Y, Yule DI. Regulation of Ca2+ release through inositol 1,4,5-trisphosphate receptors by adenine nucleotides in parotid acinar cells. Am J Physiol Gastrointest Liver Physiol 302: G97-G104, 2012. First published September 29, 2011; doi:10.1152/ajpgi.00328.2011.-Secretagogue-stimulated intracellular Ca2+ signals are fundamentally important for initiating the secretion of the fluid and ion component of saliva from parotid acinar cells. The Ca2+ signals have characteristic spatial and temporal characteristics, which are defined by the specific properties of Ca2+ release mediated by inositol 1,4,5-trisphosphate receptors (InsP(3)R). In this study we have investigated the role of adenine nucleotides in modulating Ca2+ release in mouse parotid acinar cells. In permeabilized cells, the Ca2+ release rate induced by submaximal [InsP(3)] was increased by 5 mM ATP. Enhanced Ca2+ release was not observed at saturating [InsP(3)]. The EC50 for the augmented Ca2+ release was similar to 8 mu M ATP. The effect was mimicked by nonhydrolysable ATP analogs. ADP and AMP also potentiated Ca2+ release but were less potent than ATP. In acini isolated from InsP(3)R-2-null transgenic animals, the rate of Ca2+ release was decreased under all conditions but now enhanced by ATP at all [InsP3]. In addition the EC50 for ATP potentiation increased to similar to 500 mu M. These characteristics are consistent with the properties of the InsP(3)R-2 dominating the overall features of InsP(3)R-induced Ca2+ release despite the expression of all isoforms. Finally, Ca2+ signals were measured in intact parotid lobules by multiphoton microscopy. Consistent with the release data, carbachol-stimulated Ca2+ signals were reduced in lobules exposed to experimental hypoxia compared with control lobules only at submaximal concentrations. Adenine nucleotide modulation of InsP(3)R in parotid acinar cells likely contributes to the properties of Ca2+ signals in physiological and pathological conditions.