Effects of extracellular ATP and nerve growth factor on pheochromocytoma PC12 cells.

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Effects of extracellular ATP on pheochrowxytoma PC12 and PC12h cells, and on the responses of the cells to nerve growth factor (NGF) were studied. 1) ATP inhibited the PC12h cell growth regardless with the presence or absence of NGF in the culture medium. 2) ATP enhanced the NGF-induced neurite outgrowth from PC12h cells : it increased the neurite length rather than the frequency of the neurite formation. ADP, AMP and adenosine (ADO) also showed the similar effect. Rank order of their potency was ATP>ADP>AMP=ADO. 3) ATP stimulated phosphorylation of a nuclear protein, SMP, of PC12 cells. SMP is a protein of which phosphorylation has been known to be enhanced by NGF. At lower concentration this enhancing effect was specific for ATP. At higher concentration (1 mM) AMP and ADO also showed the similar effect. 4) ATPinduced increase in cytosolic Ca^<2+> concentration of Pcl2h cells. Even in the absence of extracellular Ca^<2+>, about 40% of the maximal[Ca^<2+>]i increase was induced by ATP. ADP had the similar effect but AMP and ADO did not. 5) ATP induced a release of dopamine from PC12h cells. In the absence of extracellular Ca^<2+>, less than 10% of dopamine release detected in the presence of Ca^<2+> was observed, indicating that Ca^<2+> introduced into the cells by influx may play the major role in ATP-evoked catecholamine release. In the short term responses of the cells to ATP, adenine nucleotide specificity for ATP was quite clear. On the other hand, ATP is known to metabolized to ADP, AMP and ADO in sermcontaining culture medium and in body fluid. Therefore, the responses of the cells observed by long-term treatment with ATP may be resulted from a complex effect of ATP mediated by P_2 receptors and that of AMP and ADO mediated by Adenosine receptors.