Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems.

PACAP is a pleiotropic neuropeptide that belongs to the secretin/glucagon/VIP family. PACAP functions as a hypothalamic hormone, neurotransmitter, neuromodulator, vasodilator, and neurotrophic factor. Its structure has been remarkably conserved during evolution. The PACAP receptor is G protein-coupled with seven transmembrane domains and also belongs to the VIP receptor family. PACAP, but not VIP, binds to PAC1-R, whereas PACAP and VIP bind to VPAC1-R and VPAC2-R with a similar affinity. Despite the sizable homology of the structures of PACAP and VIP and their receptors, the distribution of these peptides and receptors is quite different. At least eight subtypes of PACAP specific, or PAC1-R, result from alternate splicing. Each subtype is coupled with specific signaling pathways, and its expression is tissue or cell specific. Although PACAP fulfills most requirements for a physiological hypothalamic hypophysiotropic hormone, it does not consistently stimulate secretion of the adenohypophysial hormones, except for stimulation of IL-6 release from the FS cells of the pituitary. The major regulatory role of PACAP in pituitary cells appears to be the regulation of gene expression of pituitary hormones and/or regulatory proteins that control growth and differentiation of the pituitary glandular cells. These effects appear to be exhibited directly and indirectly through a paracrine or autocrine action. Although PACAP stimulates the release of AVP, the physiological role of neurohypophysial PACAP remains unknown. One important action of PACAP in the endocrine system is its role as a potent secretagogue for adrenaline from the adrenal medulla through activation of TH. PACAP also stimulates the release of insulin and increases [Ca2+]i from pancreatic beta-cells at an extremely small concentration. The stage-specific expression of PACAP in testicular germ cells during spermatogenesis suggests its regulatory role in the maturation of germ cells. In the ovary, PACAP is transiently expressed in the granulosa cells of the preovulatory follicles and appears to be involved in the LH-induced cellular events in the ovary, including prevention of follicular apoptosis. In the central nervous system, PACAP acts as a neurotransmitter or neuromodulator, which has been supported by IHC and electrophysiological methods. More important, PACAP is a neurotrophic factor that may play an important role during the development of the brain. In the adult brain, PACAP appears to function as a neuroprotective factor that attenuates the neuronal damage resulting from various insults.