Procorticotrophin-releasing hormone: endoproteolytic processing and differential release of its derived peptides within AtT20 cells

Perone, Marcelo J.; Murray, Christian; Brown, Oscar A.; Gibson, S.; White, Anne; Linton, Elizabeth A.; Perkins, Anthony V.; Löwenstein, Pedro R.; Castro, María G.

doi:10.1016/s0303-7207(98)00104-x

Cited by 19 publications

(7 citation statements)

References 44 publications

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“…Alternatively, the differential post-translational endoproteolysis of the GnIH precursor might be associated with the physiological functions of GnIH and GnIH-RP-2. Recently, some bioactive peptides originating from one precursor polypeptide have been shown to be differentially processed or sorted into distinct secretory granules [30][31][32][33][34][35], which enables peptides to undergo cell-specific or tissue-specific functional targeting. These findings support a notion that proGnIH might undergo differential proteolytic processing and\or that GnIH and GnIH-RP-2 are packed into different secretory granules for subsequent release into distinct target tissues.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a cDNA encoding a novel avian hypothalamic neuropeptide exerting an inhibitory effect on gonadotropin release

et al. 2001

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We previously isolated a novel dodecapeptide containing a C-terminal -Arg-Phe-NH(2) sequence, SIKPSAYLPLRF-NH(2) (RFamide peptide), from the quail brain. This quail RFamide peptide was shown to decrease gonadotropin release from the cultured anterior pituitary and to be located at least in the quail hypothalamo-hypophysial system. We therefore designated this RFamide peptide gonadotropin inhibitory hormone (GnIH). In the present study we characterized the GnIH cDNA from the quail brain by a combination of 3' and 5' rapid amplification of cDNA ends ('RACE'). The deduced GnIH precursor consisted of 173 amino acid residues, encoding one GnIH and two putative gene-related peptide (GnIH-RP-1 and GnIH-RP-2) sequences that included -LPXRF (X=L or Q) at their C-termini. All these peptide sequences were flanked by a glycine C-terminal amidation signal and a single basic amino acid on each end as an endoproteolytic site. Southern blotting analysis of reverse-transcriptase-mediated PCR products demonstrated a specific expression of the gene encoding GnIH in the diencephalon including the hypothalamus. Furthermore, mass spectrometric analyses detected the mass numbers for matured GnIH and GnIH-RP-2, revealing that both peptides are produced from the precursor in the diencephalon as an endogenous ligand. Taken together, these results lead to the conclusion that GnIH is a hypothalamic factor responsible for the negative regulation of gonadotropin secretion. Furthermore, the presence of a novel RFamide peptide family containing a C-terminal -LPXRF-NH(2) sequence has been revealed.

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Section: Discussionmentioning

confidence: 99%

Characterization of a cDNA encoding a novel avian hypothalamic neuropeptide exerting an inhibitory effect on gonadotropin release

et al. 2001

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“…Pre-proCRH is cleaved in the rough endoplasmic reticulum to generate proCRH with a molecular mass of 18 kDa, which increases to 23 kDa after post-translational modifications (29,37). Pro-CRH undergoes endoproteolytic processing within the trans-Golgi network and secretory granules that appears to be controlled by the convertases PC1 and PC2 to generate the final 41 aa residue (4.7 kDa) CRH peptide (29,37,38). Expression of the CRH gene is controlled by a promoter region located ϳ200 bp upstream that contains the TATA box and cyclic AMP-responsive element (CRE) (29 -31).…”

Section: Overview Of Corticotropin-releasing Hormone (Crh) and Urocormentioning

confidence: 99%

Cutaneous expression of corticotropin‐releasing hormone (CRH), urocortin, and CRH receptors

et al. 2001

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Studies in mammalian skin have shown expression of the genes for corticotropin-releasing hormone (CRH) and the related urocortin peptide, with subsequent production of the respective peptides. Recent molecular and biochemical analyses have further revealed the presence of CRH receptors (CRH-Rs). These CRH-Rs are functional, responding to CRH and urocortin peptides (exogenous or produced locally) through activation of receptor(s)-mediated pathways to modify skin cell phenotype. Thus, when taken together with the previous findings of cutaneous expression of POMC and its receptors, these observations extend the range of regulatory elements of the hypothalamic-pituitary-adrenal axis expressed in mammalian skin. Overall, the cutaneous CRH/POMC expression is highly reactive to common stressors such as immune cytokines, ultraviolet radiation, cutaneous pathology, or even the physiological changes associated with the hair cycle phase. Therefore, similar to its central analog, the local expression and action of CRH/POMC elements appear to be highly organized and entrained, representing general mechanism of cutaneous response to stressful stimuli. In such a CRH/POMC system, the CRH-Rs may be a central element.

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“…The proteolytic processing of many prohormones by prohormone convertases-1/3 (PC1/3) also begins in the TGN (3). Prohormones initially cleaved in the TGN include prothyrotropin-releasing hormone (pro-TRH) (7), prosomatostatin (8), proneurotensin-neuromendin-N (9), procorticotrophin-releasing factor (10), and pro-opiomelanocortin (11)(12)(13), although some cases are controversial (14,15). Thus, we hypothesized that peptides derived from post-translational processing of a given precursor could be differentially sorted within the secretory pathway if the proteolytic processing occurs before to the sorting events.…”

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confidence: 99%

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

Perelló

Stuart

Nillni

2008

Journal of Biological Chemistry

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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.

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Procorticotrophin-releasing hormone: endoproteolytic processing and differential release of its derived peptides within AtT20 cells

Cited by 19 publications

References 44 publications

Characterization of a cDNA encoding a novel avian hypothalamic neuropeptide exerting an inhibitory effect on gonadotropin release

Characterization of a cDNA encoding a novel avian hypothalamic neuropeptide exerting an inhibitory effect on gonadotropin release

Cutaneous expression of corticotropin‐releasing hormone (CRH), urocortin, and CRH receptors

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

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