Neuropeptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), can influence diverse cellular processes over a broad temporal range. In ciliary ganglion (CG) neurons, for example, PACAP binding to high-affinity PAC1 receptors triggers transduction cascades that both rapidly modulate nicotinic receptors and synapses and support long-term survival. Since PACAP/PAC1 signaling recruits intracellular messengers and effectors that potently alter transcription, we examined its activation of the transcription factor CREB and then tested for changes in gene expression. PACAP/PAC1 signaling rapidly induced prolonged CREB activation in CG neurons by a phospholipase C -independent mechanism supported by Ca2+-influx, adenylate cyclase, and effectors, including protein kinase C (PKC) and possibly PKA. Since PACAP is abundant in the CG and released from depolarized presynaptic terminals, it is well suited to regulate gene expression relevant to neuronal and synaptic development. Gene array screens conducted using RNA from CG cultures grown with PACAP for 1/4, 24, or 96 h revealed a time-dependent pattern of > 600 regulated transcripts, including several encoding proteins implicated in synaptic function, neuronal survival, and development. The results underscore rapid, neuromodulatory, and long-term, neurotrophic consequences of PAC1 signaling in CG neurons and suggest that PACAP exerts such diverse influences by altering the expression of specific gene transcripts in a time-dependent fashion.
