Separate Cyclic AMP Sensors for Neuritogenesis, Growth Arrest and Survival of Neuroendocrine Cells [Neurobiology]

February 24th, 2014 by Emery, A. C., Eiden, M. V., Eiden, L. E.

Dividing neuroendocrine cells differentiate into a neuronal-like phenotype in response to ligands activating G protein-coupled receptors, leading to the elevation of the second messenger cyclic 3'-5'-adenosine monophosphate (cAMP). Growth factors that act at receptor tyrosine kinases, such as nerve growth factor, likewise cause differentiation. We report here that two aspects of cAMP-induced differentiation, neurite extension and growth arrest, are dissociable at the level of the sensor conveying the cAMP signal in PC12 and NS-1 cells. Following cAMP elevation, NCS/Rapgef2 is activated for signaling to ERK to mediate neuritogenesis, while Epac2 is activated for signaling to the MAP kinase p38 to mediate growth arrest. Neither action of cAMP requires transactivation of TrkA, the receptor for NGF. In fact, the differentiating effects of NGF do not require activation of any of the cAMP sensors protein kinase A, Epac, or NCS/Rapgef2, but rather depend on ERK and p38 activation via completely independent signaling pathways. Hence, cAMP- and NGF-dependent signaling for differentiation are also completely insulated from each other. Cyclic AMP and NGF also protect NS-1 cells from serum withdrawal-induced cell death, again by two wholly separate signaling mechanisms, PKA-dependent for cAMP, and PKA-independent for NGF.