Regulation of early response genes in pancreatic acinar cells: external calcium and nuclear calcium signalling aspects

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Nuclear calcium signalling has been an important topic of investigation for many years and some aspects have been the subject of debate. Our data from isolated nuclei suggest that the nuclear pore complexes (NPCs) are open even after depletion of the Ca2+ store in the nuclear envelope (NE). The NE contains ryanodine receptors (RyRs) and Ins(1,4,5)P3 receptors [Ins(1,4,5)P3Rs], most likely on both sides of the NE and these can be activated separately and independently: the RyRs by either NAADP or cADPR, and the Ins(1,4,5)P3Rs by Ins(1,4,5)P3. We have also investigated the possible consequences of nuclear calcium signals: the role of Ca2+ in the regulation of immediate early genes (IEG): c-fos, c-myc and c-jun in pancreatic acinar cells. Stimulation with Ca2+-mobilizing agonists induced significant increases in levels of expression. Cholecystokinin (CCK) (10 nM) evoked a substantial rise in the expression levels, highly dependent on external Ca2+: the IEG expression level was lowest in Ca2+-free solution, increased at the physiological level of 1 mM [Ca2+]o and was maximal at 10 mM [Ca2+]o, i.e.: 102 ± 22% and 163 ± 15% for c-fos; c-myc −73 ± 13% and 106 ± 24%; c-jun −49 ± 8% and 59 ± 9% at 1 and 10 mM of extracellular Ca2+ respectively. A low CCK concentration (10 pM) induced a small increase in expression. We conclude that extracellular Ca2+ together with nuclear Ca2+ signals induced by CCK play important roles in the induction of IEG expression.

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