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J. Biol. Chem., Vol. 283, Issue 29, 19936-19947, July 18, 2008

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Prothyrotropin-releasing Hormone Targets Its Processing Products to Different Vesicles of the Secretory Pathway^*

Mario Perello, Ronald Stuart, and Eduardo A. Nillni¹

From the Division of Endocrinology, Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island 02903 and the Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02903

Prothyrotropin-releasing hormone (pro-TRH) is initially cleaved by the prohormone convertase-1/3 (PC1/3) in the trans-Golgi network generating N- and C-terminal intermediate forms that are then packed into secretory vesicles. However, it is not known whether these peptides are differentially sorted within the secretory pathway. This is of key importance because the processing products of several prohormones fulfill different biological functions. Using AtT20 cells stably transfected with prepro-TRH cDNA, we found that two specific N- and C-terminal peptides were located in different vesicles. Furthermore, the C-terminal pro-TRH-derived peptides were more efficiently released in response to KCl and norepinephrine, a natural secretagogue of TRH. Similar sorting and secretion of N- and C-terminal peptides occurs in vivo. When we blocked the initial proteolytic processing by a mutagenic approach, the differential sorting and secretion of these peptides were prevented. In summary, our data show that pro-TRH-derived peptides are differentially sorted within the secretory pathway and that the initial cleavage in the trans-Golgi network is key to this process. This could be a common mechanism used by neuroendocrine cells to regulate independently the secretion of different bioactive peptides derived from the same gene product.

Received for publication, January 28, 2008 , and in revised form, May 5, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 DK58148 from NIDDK and R01 NS045231 from NINDS (to E. A. N.). This work was also supported by the Dr. George A. Bray Research Scholars Award Fund (to M. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 55 Claverick St., Rm. 320, Providence, RI 02903. Tel.: 401-444-5733; Fax: 401-444-6964; E-mail: Eduardo_Nillni{at}brown.edu.

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