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PACAP regulates transcription of the Ier3 gene during PC12 cell differentiation via calcium‐dependent activation of a non‐canonical (PKA‐independent) cAMP signaling pathway that activates ERK and Elk
Author(s) -
Gerdin Matthew J.,
Eiden Lee E.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.728.7
Subject(s) - forskolin , mapk/erk pathway , microbiology and biotechnology , chemistry , signal transduction , calcium , receptor , biology , biochemistry , organic chemistry
PC12 cells are a model to study PACAP‐mediated differentiation. PACAP, forskolin or KCl increase neuritogenesis in PC12 cells suggesting a role for cAMP and calcium. Neuritogenesis is ERK dependent and PACAP, forskolin or KCl increase ERK phosphorylation identifying ERK as a critical signaling node in PC12 cell neuritogenesis. Interestingly, PACAP activation of ERK is independent of PKA as it is not blocked following pharmacological inhibition of PKA or in a PC12 cell deficient in PKA, while forskolin and KCl appear PKA‐dependent. Combinatorial activation by cAMP and calcium, however, exhibits a synergistic activation of an Elk reporter whose inhibition in the presence of a PKA inhibitor is equivalent to PACAP suggesting that this combinatorial regulation unmasks a PKA‐independent signaling cassette not seen with either agent alone. Microarray analysis identified cAMP and ERK dependent genes potentially involved in PC12 cell neuritogenesis. One gene, Ier3, exhibited a similar combinatorial regulation by cAMP and calcium as seen with the Elk reporter and PACAP‐induction of Ier3 was significantly blunted by pharmacological inhibitors targeting calcium signaling, but independent of PKA. These data suggest that forskolin and KCl alone activate a PKA‐dependent signaling pathway but that co‐stimulation with both forskolin and KCl unmasks a PKA‐independent pathway, which is used by PACAP via the PAC1 receptor.