60 YEARS OF POMC: Biosynthesis, trafficking, and secretion of pro-opiomelanocortin-derived peptides

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   Figure 1

   Schematic diagram of the bovine POMC protein. The prohormone encodes multiple peptides that can be cleaved by prohormone convertases in a cell- and a time-dependent manner. ACTH, adrenocorticotropin; MSH, melanocyte-stimulating hormone; JP, joining peptide; CLIP, corticotropin-like intermediate peptide; RSP, regulated secretory pathway. Lollipop symbols represent glycosylation sites.
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   Figure 2

   An NMR confomer of the N-POMC(1–26) peptide encoding the RSP sorting signal. Note the two acidic residues, Asp¹⁰ and Glu¹⁴, and the two hydrophobic residues, Leu¹¹ and Leu¹⁸, comprising the sorting signal motif.
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   Figure 3

   Molecular model of CPE based on the crystal structure of CPD. The red areas indicate the similarity of CPE and CPD, whereas the blue areas indicate the unique areas to CPE. Note the N-POMC(1–26) sorting signal binding site composed of Arg²⁵⁵ and Lys²⁶⁰.
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   Figure 4

   Pulse–chase studies of POMC in mouse AL cells. Pituitary AL cells from WT and CPE KO mice were cultured and metabolically labeled with ³⁵S-Met for 30 min and chased for 2 h. Immunoreactive ACTH molecules were analyzed by immunoprecipitation and quantified. Note the reduced levels of ACTH made in the CPE KO cells. The overall recovery of total ACTH-IR was less in the CPE KO cells compared to the WT cells indicative of degradation (unpublished data of the authors).
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   Figure 5

   General schematic depicting the processing of bovine POMC. In the AL, PC1/3 is the primary convertase involved in the generation of 16-kDa N-POMC, ACTH, and β-LPH. A more comprehensive processing pattern is seen in the IL and hypothalamus, yielding α-MSH and β-endorphin. APB, aminopeptidase B-like; AACE, acidic ACTH-converting enzyme; CPE, carboxypeptidase E; NAT, N-acetyltransferase; PAM, peptidylglycine α-amidating monooxygenase; -END, -endorphin; JP, joining peptide; -MSH, -melanocyte-stimulating hormone; PC, prohormone convertase; Ac, acetyl; K, lysine; R, arginine. *α-MSH in humans may not occur naturally (Scott & Lowry 1974).
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   Figure 6

   Simplified schematic of the hypothalamic–pituitary axis. (A) Corticotrophs in the AL are under positive regulation by CRF released from the hypothalamus during times of stress. These cells release ACTH that causes the secretion of glucocorticoids from the adrenal cortex. Glucocorticoids then inhibit ACTH, β-LPH, and β-endorphin release in a negative feedback manner. Dopamine (DA) inhibits and CRF increases the secretion of α-MSH and β-endorphin from the melanotrophs of the IL. (B) Leptin secreted from adipocytes activates POMC neurons in the arcuate nucleus of the hypothalamus to release α-MSH and β-endorphin. See main text for other neurotransmitters and peptide hormones that help regulate the secretion of POMC-derived peptides from these tissues.

• © 2016 Society for Endocrinology