Pituitary adenylate cyclase-activating polypeptide (PACAP) promotes both survival and neuritogenesis in PC12 cells through activation of nuclear factor κB (NF-κB) pathway: Involvement of extracellular signal-regulated kinase (ERK), calcium, and c-Rel

The pituitary adenylate cyclase-activating polypeptide (PACAP) is a trophic factor that promotes neuronal survival and neurite outgrowth. However, the signaling pathways and the transcriptional mechanisms involved are not completely elucidated. Our previous studies aimed at characterizing the transcriptome of PACAP-differentiated PC12 cells revealed an increase in the expression of nuclear factor κB2 (NF-κB2) gene coding for p100/p52 subunit of NF-κB transcription factor. Here, we examined the role of the NF-κB pathway in neuronal differentiation promoted by PACAP. We first showed that PACAP-driven survival and neuritic extension in PC12 cells are inhibited following NF-κB pathway blockade. PACAP stimulated both c-Rel and p52 NF-κB subunit gene expression and nuclear translocation, whereas c-Rel down-regulation inhibited cell survival and neuritogenesis elicited by the neuropeptide. PACAP-induced c-Rel nuclear translocation was inhibited by ERK1/2 and Ca²⁺ blockers. Furthermore, the neuropeptide stimulated NF-κB p100 subunit processing into p52, indicative of activation of the NF-κB alternative pathway. Taken together, our data show that PACAP promotes both survival and neuritogenesis in PC12 cells by activating NF-κB pathway, most likely via classical and alternative signaling cascades involving ERK1/2 kinases, Ca²⁺, and c-Rel/p52 dimers.