Biologically active peptides are synthesized from large, inactive precursors by a series of co- and post- translational modifications such as proteolysis, amidation, and acetylation. The biosynthesis of peptides requires the sequential action of a set of granule- associated enzymes that includes prohormone convertases (PCI and PC2), carboxpeptidase H (CPH), peptidylglycine alpha- amidating monooxygenase (PAM), and cytochrome b561, in addition to other granule constituents. Previous studies using the intermediate pituitary have established that a coordinate regulation of proopimelanocortin (POMC), the common precursor to several peptide hormones including adenocorticotrophic hormone (ACTH), alpha-melantropin (alpha-MSH) and beta-endorphin, and the enzymes essential for POMC processing occurs following chronic stimulation or inhibition with dopaminergic agents. Most importantly, these studies indicate that ranslational effects play a major role in the more rapid regulation of POMC and processing enzymes in response to dopaminergic agents. The second goal is to determine at what stage of translation the synthesis of POMC and processing enzymes is affected. The role of the 5'- and 3'- untranslated regions of POMC, PC2 and PAM transcripts in the regulation of the biosynthesis of POMC, PC2 and PAM will be examined. the third goal is to determine the effects of dopaminergic agents on the enzymatic activity and the forms of the processing enzymes. It is clear that drug abuse affects many peptidergic systems in the brain. A number of drugs of abuse (e.g. cocaine and amphetamine) can induce changes in the synthesis of bioactive peptides in response to inhibition or stimulation of the dopaminergic systems. The role of peptidergic neurons in physiological and pharmacological processes related to drug abuse is difficult to define due to the complexity of the peptidergic system in vivo. Therefore, by using a relatively homogeneous system such as melanotropes of the intermediate pituitary to study translational regulation of prohormone and processing enzymes, I hope to provide some insight into the adjustments peptidergic systems make in response to dopaminergic agents.
| Oyarce, A M; Steveson, T C; Jin, L et al. (2001) Dopamine beta-monooxygenase signal/anchor sequence alters trafficking of peptidylglycine alpha-hydroxylating monooxygenase. J Biol Chem 276:33265-72 |
| Oyarce, A M; Eipper, B A (2000) Cell type-specific storage of dopamine beta-monooxygenase. J Biol Chem 275:3270-8 |
