The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily

The pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon sup erfamily includes nine hormones in humans that are related by structure, di stribution (especially the brain and gut), function (often by activation of cAMP), and receptors (a subset of seven-transmembrane receptors). The nine hormones include glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, glucose -dependent insulinotropic polypeptide (GIP), GH-releasing hormone (GRF), pe ptide histidine-methionine (PHM), PACAP, secretin, and vasoactive: intestin al polypeptide (VIP). The origin of the ancestral superfamily members is at least as old as the invertebrates; the most ancient and tightly conserved members are PACAP and glucagon. Evidence to date suggests the superfamily b egan with a gene or exon duplication and then continued to diverge with som e gene duplications in vertebrates. The function of PACAP is considered in detail because it is newly (1989) discovered; it is tightly conserved (96% over 700 million years); and it is probably the ancestral molecule. The div erse functions of PACAP include regulation of proliferation, differentiatio n, and apoptosis in some cell populations. In addition, PACAP regulates met abolism and the cardiovascular, endocrine, and immune systems, although the physiological event(s) that coordinates PACAP responses remains to be iden tified.