Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse?

It has been known for more than a decade that the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) is co-stored with acetylcholine in the splanchnic nerve terminals innervating the adrenal medulla. Both transmitters are robust secretagogues for catecholamine release from chromaffin cells. Here, we review the unique contribution of PACAP to the functioning of the splanchnic-adrenal synapse in stress. While acetylcholine is released across a wide range of firing frequencies, PACAP is released only at high frequencies of stimulation, and its role in the regulation of epinephrine secretion and biosynthesis is highly specialized. PACAP is responsible for long-term catecholamine secretion using secretory mechanisms different from the rapidly desensitizing depolarization evoked by acetylcholine through nicotinic receptor activation. PACAP signaling also maintains catecholamine synthesis required for sustained secretion during prolonged stress via induction of the enzymes TH and PNMT, and enhances transcription of additional secreted molecules found in chromaffin cells that alter further secretion through both autocrine and paracrine mechanisms. PACAP thus mediates chromaffin cell plasticity via functional encoding of cellular experience. These features of PACAP action at the splanchnic-adrenal synapse may be paradigmatic for the general actions of neuropeptides as effectors of stimulus-secretion-synthesis coupling in stress.