Pituitary adenylate cyclase-activating polypeptide and its receptors: Fromstructure to functions

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino ac id peptide that was first isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP formation in anterior pituitary cell s. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-glucagon-gr owth hormone releasing factor-secretin superfamily. The sequence of PACAP h as been remarkably well conserved during the evolution from protochordate t o mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and periphe ral organs, notably in the endocrine pancreas, gonads, and respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide whose activity remains unknown. Two t ypes of PACAP binding sites have been characterized. Type I binding sites e xhibit a high affinity for PACAP and a much lower affinity for VIP whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cl oning of PACAP receptors has shown the existence of three distinct receptor subtypes, the PACAP-specific PAC1 receptor, which is coupled to several tr ansduction systems, and the two PACAP/VIP-indifferent VPAC1 and VPAC2 recep tors, which are primarily coupled to adenylyl cyclase. PAC1 receptors are p articularly abundant in the brain and pituitary and adrenal glands whereas VPAC receptors are expressed mainly in the lung, liver, and testis. The wid e distribution of PACAP and PACAP receptors has led to an explosion of stud ies aimed at determining the pharmacological effects and biological functio ns of the peptide. This report reviews the current knowledge concerning the multiple actions of PACAP in the central nervous system and in various per ipheral organs including the endocrine glands, the airways, and the cardiov ascular and immune systems, as well as the different effects of PACAP on a number of tumor cell types.