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A more recent version of this article appeared on June 1, 2005
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Submitted on January 25, 2005
Revised on March 22, 2005
Accepted on March 29, 2005
Is Regulated by Ca2+ Influx and PtdIns(4,5)P2 in Differentiated PC12 Cells
Departamento de Bioquímica y Biología Molecular (A), Facultad de Veterinaria, Universidad de Murcia, E-30100 Murcia, Spain
Monitoring Editor: John York
Signal transduction through PKCs strongly depends on their subcellular localization. Here, we investigate the molecular determinants of PKC
localization using a model system of NGF-differentiated PC12 cells and extracellular stimulation with ATP. Strikingly, the Ca2+ influx, initiated by the ATP stimulation of P2X receptors, rather than the Ca2+ released from the intracellular stores, was the driving force behind the translocation of PKC to the plasma membrane. Furthermore, the localization process depended on two regions of the C2 domain: the Ca2+-binding region and the lysine-rich cluster, which bind Ca2+ and PtdIns(4,5)P2, respectively. It was demonstrated that diacylglycerol was not involved in the localization of PKC through its C1 domain, and in lieu, the presence of PtdIns(4,5)P2 increased the permanence of PKC in the plasma membrane. Finally, it was also shown that ATP cooperated with NGF during the differentiation process of PC12 cells by increasing the length of the neurites, an effect that was inhibited when the cells were incubated in the presence of a specific inhibitor of PKC, suggesting a possible role for this isoenzyme in the neural differentiation process. Overall, these results show a novel mechanism of PKC activation in differentiated PC12 cells, where Ca2+ influx, together with the endogenous PtdIns(4,5)P2, anchor PKC to the plasma membrane through two distinct motifs of its C2 domain, leading to enzyme activation.
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