Regulation of a Post-Translational Peptide Acetyltransferase: Strategies for Selectively Modifying the Biological Activity of Neural and Endocrine Peptides

摘要

The broad objective of this research is to develop new strategies for pharmacologically modifying synaptic transmission by peptidergic neurons. It is based on the principal that post-translational processing defines the biological activity of neuropeptides and uses the Beta-endorphin processing pathway as a model for study. We examined the functional consequences of Beta-endorphin processing, demonstrating that C-terminal shortening of Beta-endorphin-1-31 to Beta-endorphin-1-27 augments its central hypotensive potency. This contrasts studies on analgesia where Beta-endorphin-1-27 is a weak agonist, but a highly potent antagonist, and indicates that peptide processing can produce entirely different changes in bioactivity depending upon the postsynaptic receptors which mediate the response. The second objective characterized Beta-endorphin processing in human brain, demonstrating that Beta-endorphin-1-31 is the predominant form; significant amounts of Beta-endorphin-1-27 and -1-26 and small amounts of N-acetylated Beta-endorphin peptides were also present. Thus, despite important differences in primary structure, Beta-endorphin is processed similarly in both human and rat brain, thereby confirming the rat as a valid model for investigating the function and regulation of Beta-endorphin processing. (aw)