Implication of pituitary adenylate cyclase-activating polypeptide (PACAP) for neuroprotection of nicotinic acetylcholine receptor signaling in PC12 cells.

Pituitary adenylate cyclase-activating polypeptide (PACAP) functions as a neurotrophic factor through PAC1-R, PACAP-specific receptor, in the central nervous system. On the other hand, by interacting with nicotinic acetylcholine receptor (nAChR), nicotine exhibits several neuroprotective effects. Since the relevance of PACAP and nAChR signaling has not been reported so far, we attempted to investigate their relevance in terms of neuroprotection in PC12 cells. Regarding the effect of nicotine on PACAP gene expression, nicotine increased its mRNA level in time-dependent and dose-dependent manners in the PC12 cells differentiated with nerve growth factor (NGF). In addition, luciferase reporter assay demonstrated that nicotine treatment significantly augments the promoter activity of PACAP gene. Since PAC1-R mRNA expression was induced by NGF, PACAP exhibited neuroprotective effect against tunicamycin-induced cell death in the differentiated PC12 cells. Nicotine also exhibited the neuroprotective effect, which was significantly attenuated by Max.d.4 (PAC1-R specific antagonist). These results suggest that the increment of PACAP gene expression due to nicotine treatment might be involved in the neuroprotection by nicotine.