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Biosynthesis of Proopiomelanocortin-Derived Peptides in Prohormone Convertase 2 and 7B2 Null Mice

Department of Biochemistry and Molecular Biology (V.L., L.J.-M., I.L.), Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112; and Département de Pharmacologie (R.De., R.Da.), Faculté de Mèdecine et Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada JIH 5N4

Address all correspondence and requests for reprints to: Iris Lindberg, Ph.D., Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, Louisiana 70112. E-mail: ilindb{at}LSUHSC.edu.

Prohormone convertases (PCs) are thought to represent the major proteinases involved in the biosynthetic processing of peptide hormone precursors to bioactive peptide products. The maturation of PC2 requires the aid of a helper protein, 7B2, in order for the zymogen to become an active enzyme species. The 7B2 and PC2 nulls should thus be functionally equivalent with regard to deficits in precursor processing. In this article, we have examined this proposition through the study of proopiomelanocortin (POMC) biosynthesis and granule content in both null models. RIA data indicate that both PC2 and 7B2 nulls lack pituitary -MSH; interestingly, 7B2 nulls are still able to generate ß-endorphin from ß-lipotropin, whereas PC2 nulls contain little if any ß-endorphin. Labeling experiments demonstrate a build-up of POMC, high molecular weight intermediates, and intact ACTH, as well as the disappearance of -MSH, in both null models. Electron microscopy of neurointermediate lobe melanotrophs reveals the presence of a significantly greater number of secretory granules in both 7B2 and PC2 nulls compared with wild-type controls. However, PC2 null melanotrophs contain twice as many granules as 7B2 null melanotrophs. Another difference between the two null models is a relatively enhanced accumulation of precursors in the PC2 null compared with the 7B2 null; these include not only PC2 substrates, but also presumed PC1 substrates. These data indicate that the two nulls are not phenotypically equivalent.

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