The Regulation of a Post-Translational Peptide Acetyltransferase: Strategies for Selectively Modifying the Biological Activity of Neural and Endocrine Peptides
Annual rept. 1 Feb 1988-31 Jan 1989
UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD
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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.