Biosynthesis and function of VIP and oxytocin: mechanisms of C-terminal amidation, oxytocin secretion and transport.

Abstract

In this review, we provide the current status of research on vasoactive intestinal peptide (VIP) and oxytocin, typical C-terminal α-amidated peptide hormones, including their precursor protein structures, processing and C-terminal α-amidation, and the recently identified mechanisms of regulation of oxytocin secretion and its transportation through the blood brain barrier. More than half of neural and endocrine peptides, such as vasoactive intestinal peptide (VIP) and oxytocin, have the α-amide structure at their C-terminus, which is generally essential for biological activities. We have studied the synthesis and function of C-terminal α-amidated peptides, including VIP and oxytocin, since the 1980s. Human VIP mRNA encoded not only VIP but also another related C-terminal α-amidated peptide, PHM-27 (peptide having amino-terminal histidine, carboxy-terminal methionine amide and 27 amino acid residues). The human VIP/PHM-27 gene was composed of seven exons and regulated synergistically by cyclic AMP and protein kinase C pathways. VIP has an essential role in glycemic control using transgenic mouse technology. The peptide C-terminal α-amidation proceeded through a two-step mechanism catalyzed by two different enzymes encoded in a single mRNA. In the oxytocin secretion from the hypothalamus/the posterior pituitary, the CD38-cyclic ADP-ribose signal system, that was first established in the insulin secretion from pancreatic β cells of the islets of Langerhans, was found to be essential. A possible mechanism involving receptor for advanced glycation end-products (RAGE) of the oxytocin transportation from the blood stream into the brain through the blood-brain barrier has also been suggested.