The Regulation of a Post-Translational Peptide Acetyltransferase: Strategies for Selectively Modifying the Biological Activity of Neural and Endocrine Peptides
Final rept. 1 Feb 1986-30 Jun 1990
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 pepti-dergic neurons. It is based on the principal that post-trans-lational processing determines the biological activity of neural and endocrine peptides and uses the beta-endorphin processing pathway as a model for study. Five primary objectives were met during the course of this research. First, we found that post-translational processing enzymes are selectively and individually regulated, which indicates that certain processing enzymes serve a rate limiting role in peptide biosynthesis, while others do not. Second, pharmacologic agents targeted on cell surface receptors selectively regulate beta-endorphin processing enzymes, producing distinct changes in the molecular forms and, hence, the biological activities of the beta-endorphin peptides released from the pituitary gland. Third, brain beta-endorphin processing is also regulated through receptor activation although, in general, it appears to be more resistant to this strategy, emphasizing the need to develop agents which control peptide processing through direct enzyme inhibition or activation. Fourth, we characterized the beta-endorphin processing.