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At least two important neurotransmitters are released by innervating preganglionic neurons to stimulate exocytosis in the chromaffin cell\u2014acetylcholine (ACh) and pituitary adenylate cyclase activating polypeptide (PACAP). Although PACAP is widely acknowledged as an important secretagogue in this system, the pathway coupling PACAP stimulation to chromaffin cell secretion is poorly understood. The goal of this study is to address this knowledge gap. Here, it is shown that PACAP activates a G\u03b1s-coupled pathway that must signal through phospholipase C \u03b5 (PLC\u03b5) to drive Ca2+ entry and exocytosis. PACAP stimulation causes a complex pattern of Ca2+ signals in chromaffin cells, leading to a sustained secretory response that is kinetically distinct from the form stimulated by ACh. Exocytosis caused by PACAP is associated with slower release of peptide cargo than exocytosis stimulated by ACh. Importantly, only the secretory response to PACAP, not ACh, is eliminated in cells lacking PLC\u03b5 expression. The data show that ACh and PACAP, acting through distinct signaling pathways, enable nuanced and variable secretory outputs from chromaffin cells.<\/jats:p>","DOI":"10.1085\/jgp.202213180","type":"journal-article","created":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T02:20:32Z","timestamp":1668824432000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["PACAP and acetylcholine cause distinct Ca2+ signals and secretory responses in chromaffin cells"],"prefix":"10.1085","volume":"155","author":[{"given":"Alina","family":"Morales","sequence":"first","affiliation":[{"name":"Department of Neurosciences, University of Toledo, Toledo, OH, USA 1"},{"name":"Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA 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