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Research Article Free access | 10.1172/JCI118760

Chromogranin A processing and secretion: specific role of endogenous and exogenous prohormone convertases in the regulated secretory pathway.

N L Eskeland, A Zhou, T Q Dinh, H Wu, R J Parmer, R E Mains, and D T O'Connor

Department of Medicine and Center for Molecular Genetics, University of California, San Diego, USA.

Find articles by Eskeland, N. in: JCI | PubMed | Google Scholar

Department of Medicine and Center for Molecular Genetics, University of California, San Diego, USA.

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Department of Medicine and Center for Molecular Genetics, University of California, San Diego, USA.

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Department of Medicine and Center for Molecular Genetics, University of California, San Diego, USA.

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Department of Medicine and Center for Molecular Genetics, University of California, San Diego, USA.

Find articles by Parmer, R. in: JCI | PubMed | Google Scholar

Department of Medicine and Center for Molecular Genetics, University of California, San Diego, USA.

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Department of Medicine and Center for Molecular Genetics, University of California, San Diego, USA.

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Published July 1, 1996 - More info

Published in Volume 98, Issue 1 on July 1, 1996
J Clin Invest. 1996;98(1):148–156. https://doi.org/10.1172/JCI118760.
© 1996 The American Society for Clinical Investigation
Published July 1, 1996 - Version history
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Abstract

Chromogranins A and B and secretogranin II are a family of acidic proteins found in neuroendocrine secretory vesicles; these proteins contain multiple potential cleavage sites for proteolytic processing by the mammalian subtilisin-like serine endoproteases PC1 and PC2 (prohormone convertases 1 and 2), and furin. We explored the role of these endoproteases in chromogranin processing in AtT-20 mouse pituitary corticotropes. Expression of inducible antisense PC1 mRNA virtually abolished PC1 immunoreactivity on immunoblots. Chromogranin A immunoblots revealed chromogranin A processing, from both the NH2 and COOH termini, in both wild-type AtT-20 and AtT-20 antisense PC1 cells. After antisense PC1 induction, an approximately 66-kD chromogranin A NH2-terminal fragment as well as the parent chromogranin A molecule accumulated, while an approximately 50 kD NH2-terminal and an approximately 30 kD COOH-terminal fragment declined in abundance. Chromogranin B and secretogranin II immunoblots showed no change after PC1 reduction. [35S]Methionine/cysteine pulse-chase metabolic labeling in AtT-20 antisense PC1 and antisense furin cells revealed reciprocal changes in secreted chromogranin A COOH-terminal fragments (increased approximately 82 kD and decreased approximately 74 kD forms, as compared with wild-type AtT-20 cells) indicating decreased cleavage, while AtT-20 cells overexpressing PC2 showed increased processing to and secretion of approximately 71 and approximately 27 kD NH2-terminal chromogranin A fragments. Antisense PC1 specifically abolished regulated secretion of both chromogranin A and beta-endorphin in response to the usual secretagogue, corticotropin-releasing hormone. Moreover, immunocytochemistry demonstrated a relative decrease of chromogranin A in processes (where regulated secretory vesicles accumulate) of AtT-20 cells overexpressing either PC1 or PC2. These results demonstrate that chromogranin A is a substrate for the endogenous endoproteases PC1 and furin in vivo, and that such processing influences its trafficking into the regulated secretory pathway; furthermore, lack of change in chromogranin B and secretogranin II cleavage after diminution of PCl suggests that the action of PC1 on chromogranin A may be specific within the chromogranin/secretogranin protein family.

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