We examined the role of second messengers during the neuritogenesis that accompanies neuronal differentiation in a neuroblastoma × glioma hybrid cell line (NG108-15). NG108-15 cells extended neurites after treatment with dibutyryl cyclic AMP. This dibutyryl cyclic AMP treatment evoked the synthesis of voltage-dependent Ca2+ channel proteins in the cells. The number of neurites was decreased by Ca2+ influx under condition of high K+. Interestingly, the increase of neurites stimulated by dibutyryl cyclic AMP and the decrease of neurites caused by high K+ were both reversible. This is the first study to demonstrate that cyclic AMP regulates a negative feedforward system for neuritogenesis, which links with Ca2+ signaling. Such a dual role of cyclic AMP may play an important part in precise neurite targeting.
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