The neuroprotective actions of PACAP (pituitary adenylate cyclase-activating polypeptide) in vitro and in vivo suggest that activation of its cognate G protein coupled receptor PAC1 or downstream signaling molecules,and thus activation of PACAP target genes, could be of therapeutic benefit. Here, we show that cultured rat cortical neurons predominantly expressed the PAC1hop and null variants. PACAP receptor activation resulted in the elevation of the two second messengers cAMP and Ca(2+) and expression of the putative neuroprotectant stanniocalcin 1(STC1). PACAP signaling to the STC1 gene proceeded through the extracellular signal-regulated kinases 1 and 2(ERK1/2), but not through the cAMP-dependent protein kinase (PKA), and was mimicked by the adenylate cyclase activator forskolin. PACAP- and forskolin-mediated activation of ERK1/2 occurred through cAMP, but not PKA.These results suggest that STC1 gene induction proceeds through cAMP and ERK1/2, independently of PKA, the canonical cAMP effector. In contrast, PACAP signaling to the BDNF gene proceeded through PKA, suggesting that two different neuroprotective cAMP pathways co-exist in differentiated cortical neurons. The selective activation of a potentially neuroprotective cAMP-dependent pathway different from the canonical cAMP pathway used in many physiological processes, such as memory storage, has implications for pharmacological activation of neuroprotection in vivo.