Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues

More than 20 yr ago, in an elegant series of pulsechase studies, Steiner and Oyer (1) demonstrated that insulin is synthesized in pancreatic islet cells as part of a larger molecule, proinsulin. Since that time, the concept that bioactive peptides are derived from larger precursors has become firmly established (2–4). Over the same period, the definitive structures of the majority of precursors of biologically active peptides have been fully characterized, both by classical protein sequence studies and more recently by recombinant DNA techniques (for reviews see Refs. 4–6). To yield biologically active products, precursors commonly undergo a series of highly organized posttranslational events, including selective proteolytic cleavage and other enzymatic modifications (e.g., phosphorylation, β-amidation, acetylation) which take place within specific membrane-bounded compartments. A number of precursor polypeptides contain within their structure amino acid sequences which have quite diverse biological actions depending on the extent of processing. Second, different precursor molecules can contain identical or very similar sequences. A striking example of both these phenomena is found in the family of prohormones which are processed to yield the opioid peptides, POMC, proenkephalin A (proenkephalin), and proenkephalin B (prodynorphin) (for reviews see Refs. 6–8). A third common feature of precursor processing, and again one described for all three opioid prohormones, is that of tissue-specific differences in their patterns of maturation. Proenkephalin in the brain is largely processed to the pentapeptide enkephalins (9), whereas in the adrenal the majority of enkephalin-like immunoreactivity appears to be of higher molecular weight (4–10 K) (9). Similarly, prodynorphin in the hypothalamus and pituitary neural lobe is processed to smaller forms, principally dynorphin 1-8 and dynorphin 1-17 (10), while in the anterior pituitary larger immunoreactive forms (4–6 K) predominate. These tissue-specific patterns of precursor processing perhaps reflect quite distinct neurotransmitter (central nervous system) and endocrine/paracrine (peripheral tissue) physiological roles for these peptides.