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

Abstract

Prothyrotropin-releasing hormone (pro-TRH) is initiallycleaved by the prohormone convertase-1/3 (PC1/3) in the transGolgi 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.

Thyrotropin-releasing hormone overexpression induces structural changes of the left ventricle in the normal rat heart

“…In contrast, although there was a tendency, no significant differences were observed in PC1 gene expression between the groups (Fig. 1C), even though Perello et al (20) have reported that PC1 is a specific convertase involved in proTRH processing as a regulator step in TRH activity in many tissues.…”

The sorting of proglucagon to secretory granules is mediated by carboxypeptidase E and intrinsic sorting signals

“…An increase in the sorting efficiency of proglucagon after cleavage at K70R71 in the Golgi would be similar to the observations with prothyrotropin-releasing hormone (pro-TRH), where processing by PC1/3 enhances the sorting of pro-TRH-derived peptides into granules (Mulcahy et al 2005). Future experiments will investigate more closely the role of processing in proglucagon sorting, and the possibility that the products of this initial processing, glicentin and the major proglucagon fragment (MPGF) are sorted into different granule populations, again in a pattern similar to that of pro-TRH sorting (Perello et al 2008).…”

Two Dipolar α-Helices within Hormone-encoding Regions of Proglucagon Are Sorting Signals to the Regulated Secretory Pathway

“…That the sequences of glucagon and GLP-1 are highly conserved (32) lends evidence to this reasoning. This is in contrast to pro-thyrotropin-releasing hormone, where PC1/3-mediated processing early in the secretory pathway is required for efficient sorting to distinct subpopulations of granules (61,62).…”