Cooperation in signal transduction of extracellular guanosine 5′ triphosphate and nerve growth factor in neuronal differentiation of PC12 cells

Guanosine 5' triphosphate (GTP), acting synergistically with the nerve growth factor (NGF), enhances the proportion of neurite-bearing cells in cultures of PC12 rat pheochromocytoma cells. We studied the transduction mechanisms activated by GTP in PC12 cells and found that addition of GTP (100 microM) increased intracellular calcium concentration ([Ca(2+)](i)) in cells that were between 60 and 70% confluent. Addition of GTP also enhanced activation of NGF-induced extracellular regulated kinases (ERKs) and induced Ca(2+) mobilization. This mobilization, due to the activation of voltage-sensitive and ryanodine-sensitive calcium channels, as well as pertussis toxin-sensitive purinoceptors, modulates Ca(2+)-activated K(+) channels not involved in activation of ERKs. The results presented here indicate that GTP-triggered [Ca(2+)](i) increase may be a key event in GTP signal transduction, which can modulate activity of ERKs. The physiological importance of the GTP effect lies in its capacity to interact with the NGF-activated pathway to enhance neurite outgrowth from PC12 cells.