GPCR‐Gs‐mediated cyclic AMP signaling for neuritogenesis, growth arrest, and cell survival is parcellated among the cAMP sensors NCS/Rapgef2, Epac, and PKA (843.7)

Ligands that elevate cAMP through Gs‐coupled GPCR activation have profound effects on the differentiation of neuroendocrine cells. Using the PC12 cell subclone NS‐1, we found that cAMP‐induced neurite extension, cAMP‐induced growth arrest, and cAMP‐dependent cell survival are all dissociable at the level of the cAMP sensor through which signaling occurs. Previously, we showed that the protein product of the Rapgef2 gene (NCS/Rapgef2) is activated by cAMP and is coupled to the activation of the Rap1‐BRAF‐MEK‐ERK signaling cascade necessary for cAMP‐dependent neuritogenesis (Emery and Eiden, FASEB J. 26, 3199, 2012; Emery et al., Sci. Signal. 6, ra51, 2013). Cyclic AMP elevation also causes Epac (Rapgef3/4) activation, which we now find leads to activation of both Rap1 and the MAP kinase p38. Surprisingly, these two downstream effectors of Epac appear to be arranged in separate signaling pathways, since p38‐dependent growth arrest initiated by Epac was not affected by inhibition of Epac‐dependent Rap1 activation. Thus, in NS‐1 cells, cAMP‐dependent growth arrest is wholly dependent on Epac‐p38 signaling and does not require NCS/Rapgef2‐ERK or PKA‐CREB activity. Finally, we found that cAMP protects NS‐1 cells from serum withdrawal‐induced cell death, also by a wholly separable signaling mechanism, which is PKA‐dependent and does not require the activation of either NCS/Rapgef2 or Epac.Grant Funding Source: Supported by NIMH‐IRP project ZO1‐MH002386