Pituitary adenylate cyclase-activating polypeptide

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been origina lly isolated from the sheep hypothalamus on the basis of its ability to sti mulate cAMP formation in anterior pituitary cells. Post-translational proce ssing of the PACAP precursor generates two biologically active molecular fo rms. PACAP38 and PACAP27, and a novel peptide called PACAP-related peptide whose activity remains unknown. The primary structure of PACAP has been rem arkably conserved during evolution, from protochordates to mammals, suggest ing that the peptide exerts important activities throughout the vertebrate phylum. The sequence of PACAP27 exhibits substantial similarities with thos e of vasoactive intestinal polypeptide (VIP), glucagon and secretin. The ge ne encoding the PACAP precursor is widely expressed in the brain and in var ious peripheral organs, notably in endocrine glands, the gastro-intestinal and uro-genital tracts and the respiratory system. In vivo and in vitro stu dies have shown that PACAP exerts multiple activities as a hormone, neuroho rmone, neurotransmittor or trophic factor. For instance, PACAP triggers the release of insulin and glucagon, activates steroidogenesis in the adrenal gland and gonads, and stimulates the secretion of most hypophysial cells. P ACAP exerts a potent relaxant activity on smooth muscle fibers in blood ves sels, lung and gut. In the brain, PACAP stimulates the electrical activity of various populations of neurons and increase tyrosine hydroxylase gene ex pression. Recent studies have shown that PACAP exerts a trophic activity du ring ontogenesis, notably in the adrenal medulla and in the central nervous system. The biological effects of PACAP are mediated through three distinc t receptor subtypes which exhibit differential affinities for PACAP and VIP . The PAC1 receptor, which shows high selectivity for PACAP, is coupled to several transduction systems. In contrast, VPAC1 and VPAC2, which bind with the same affinity PACAP and VIP, are mainly coupled to the adenylyl cyclas e pathway. The bronchodilatator and vasorelaxant effects of PACAP, as well as the antiproliferative and neuroprotective actions of the peptide, make i t a valuable target for new drug development.