Partial inhibition of SERCA is responsible for extracellular Ca2+ dependence of AlF4--induced [Ca2+]i oscillations in rat pancreatic acinar cells

AlF4- is known to generate oscillations in intracellular Ca2+ concentration ([Ca2+](i)) by activating G proteins in many cell types. However, in rat pancreatic acinar cells, AlF4--evoked [Ca2+](i) oscillations were reported to be dependent on extracellular Ca2+, which contrasts with the [Ca2+](i) oscillations induced by cholecystokinin (CCK). Therefore, we investigated the mechanisms by which AlF4- generates extracellular Ca2+-dependent [Ca2+](i) oscillations in rat pancreatic acinar cells. AlF4--induced [Ca2+](i) oscillations were stopped rapidly by the removal of extracellular Ca2+ and were abolished on the addition of 20 mM caffeine and 2 muM thapsigargin, indicating that Ca2+ influx plays a crucial role in maintenance of the oscillations and that an inositol 1,4,5-trisphosphate-sensitive Ca2+ store is also required. The amount of Ca2+ in the intracellular Ca2+ store was decreased as the AlF4--induced [Ca2+](i) oscillations continued. Measurement of Ca-45(2+) influx into isolated microsomes revealed that AlF4- directly inhibited sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The activity of plasma membrane Ca2+-ATPase during AlF4- stimulation was not significantly different from that during CCK stimulation. After partial inhibition of SERCA with 1 nM thapsigargin, 20 pM CCK-evoked [Ca2+](i) oscillations were dependent on extracellular Ca2+. This study shows that AlF4- induces [Ca2+](i) oscillations, probably by inositol 1,4,5-trisphosphate production via G protein activation but that these oscillations are strongly dependent on extracellular Ca2+ as a result of the partial inhibition of SERCA.