Pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed in the parasympathetic ciliary ganglion (CG) and modulates nicotinic acetylcholine receptor function. PACAP also provides trophic support, promoting partial survival of CG neurons in culture and full survival when accompanied by membrane depolarization. We probed the adenylate cyclase (AC) and phospholipase-C (PLC) transduction cascades stimulated by PACAP to determine their respective roles in supporting neuronal survival and examined their interaction with signals generated by membrane activity. While PLC-dependent signaling was dispensable, AC-generated signals proved critical for PACAP to support neuronal survival. Specifically, PACAP-supported survival was mimicked by 8Br-cAMP and blocked by inhibiting either PKA or the phosphorylation of mitogen-activated protein kinase (MAPK). The ability of PACAP to promote survival was additionally dependent on spontaneous activity as blocking Na+ or Ca2+ channel currents completely abrogated trophic effects. Our results underscore the importance of coordinated MAPK- and activity-generated signals in transducing neuropeptide-mediated parasympathetic neuronal survival.
