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

Previous studies have suggested that salivary amylase and proline-rich protein are sorted differently when expressed in AtT-20 cells (Castle, A.M., L.E. Stahl, and J.D. Castle. 1992. J. Biol. Chem. 267:13093– 13100; Colomer, V., K. Lal, T.C. Hoops, and M.J. Rindler. 1994.EMBO (Eur. Mol. Biol. Organ.) J. 13:3711– 3719). We now show that both exocrine proteins behave similarly and enter the regulated secretory pathway as judged by immunolocalization and secretagogue- dependent stimulation of secretion. Analysis of stimulated secretion of newly synthesized proline-rich protein, amylase, and endogenous hormones indicates that the exogenous proteins enter the granule pool with about the same efficiency as the endogenous hormones. However, in contrast to the endogenous hormones, proline-rich protein and amylase are progressively removed from the granule pool during the process of granule maturation such that only small portions remain in mature granules where they colocalize with the stored hormones. The exogenous proteins that are not stored are recovered from the incubation medium and are presumed to have undergone constitutive-like secretion. These results point to a level of sorting for regulated secretion after entry of proteins into forming granules and indicate that retention is essential for efficient storage. Consequently, the critical role of putative sorting receptors for regulated secretion may be in retention rather than in granule entry.

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Effects of Chromogranin A and B Association on the Anion Channel Function in the Regulated Secretory Pathway

Biophysical Journal ◽

10.1016/j.bpj.2018.11.385 ◽

2019 ◽

Vol 116 (3) ◽

pp. 63a

Author(s):

Sutonuka Bhar ◽

Gaya P. Yadav ◽

Mahesh S. Chandak ◽

Qiu-Xing Jiang

Keyword(s):

Chromogranin A ◽

Secretory Pathway ◽

Anion Channel ◽

Channel Function ◽

Regulated Secretory Pathway

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Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice

Journal of Endocrinology ◽

10.1530/joe-16-0370 ◽

2017 ◽

Vol 232 (2) ◽

pp. 137-153 ◽

Cited By ~ 4

Author(s):

Kechun Tang ◽

Teresa Pasqua ◽

Angshuman Biswas ◽

Sumana Mahata ◽

Jennifer Tang ◽

...

Keyword(s):

Tissue Damage ◽

Muscle Function ◽

Chromogranin A ◽

Secretory Pathway ◽

Treadmill Exercise ◽

Tubular Aggregates ◽

Skeletal Muscle Function ◽

Regulated Secretory Pathway ◽

Exercise Induced ◽

Stimulation Of

Chromogranin A (CgA) is widely expressed in endocrine and neuroendocrine tissues as well as in the central nervous system. We observed CgA expression (mRNA and protein) in the gastrocnemius (GAS) muscle and found that performance of CgA-deficient Chga-KO mice in treadmill exercise was impaired. Supplementation with CgA in Chga-KO mice restored exercise ability suggesting a novel role for endogenous CgA in skeletal muscle function. Chga-KO mice display (i) lack of exercise-induced stimulation of pAKT, pTBC1D1 and phospho-p38 kinase signaling, (ii) loss of GAS muscle mass, (iii) extensive formation of tubular aggregates (TA), (iv) disorganized cristae architecture in mitochondria, (v) increased expression of the inflammatory cytokines Tnfα, Il6 and Ifnγ, and fibrosis. The impaired maximum running speed and endurance in the treadmill exercise in Chga-KO mice correlated with decreased glucose uptake and glycolysis, defects in glucose oxidation and decreased mitochondrial cytochrome C oxidase activity. The lack of adaptation to endurance training correlated with the lack of stimulation of p38MAPK that is known to mediate the response to tissue damage. As CgA sorts proteins to the regulated secretory pathway, we speculate that lack of CgA could cause misfolding of membrane proteins inducing aggregation of sarcoplasmic reticulum (SR) membranes and formation of tubular aggregates that is observed in Chga-KO mice. In conclusion, CgA deficiency renders the muscle energy deficient, impairs performance in treadmill exercise and prevents regeneration after exercise-induced tissue damage.

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Depletion of Carboxypeptidase E, a Regulated Secretory Pathway Sorting Receptor, Causes Misrouting and Constitutive Secretion of Proinsulin and Proenkephalin, But Not Chromogranin A

Endocrinology ◽

10.1210/endo.139.4.5951 ◽

1998 ◽

Vol 139 (4) ◽

pp. 2137-2145 ◽

Cited By ~ 32

Author(s):

Emmanuel Normant ◽

Y. Peng Loh

Keyword(s):

Chromogranin A ◽

Secretory Pathway ◽

Carboxypeptidase E ◽

Constitutive Secretion ◽

Sorting Receptor ◽

Regulated Secretory Pathway

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The Role of Dibasic Residues in Prohormone Sorting to the Regulated Secretory Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m009613200 ◽

2000 ◽

Vol 276 (9) ◽

pp. 6140-6150 ◽

Cited By ~ 35

Author(s):

Sylvain Feliciangeli ◽

Patrick Kitabgi ◽

Jean-Noël Bidard

Keyword(s):

Secretory Pathway ◽

Regulated Secretory Pathway

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Carboxypeptidase E, an essential element of the regulated secretory pathway, is expressed and partially co-localized with chromogranin A in chicken thymus

Cell and Tissue Research ◽

10.1007/s00441-009-0830-x ◽

2009 ◽

Vol 337 (3) ◽

pp. 371-379 ◽

Cited By ~ 4

Author(s):

Xiaodong Zhang ◽

James Zhu ◽

Y. Peng Loh ◽

Luc R. Berghman

Keyword(s):

Chromogranin A ◽

Secretory Pathway ◽

Essential Element ◽

Carboxypeptidase E ◽

Chicken Thymus ◽

Regulated Secretory Pathway

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Determinants for chromogranin A sorting into the regulated secretory pathway are also sufficient to generate granule-like structures in non-endocrine cells

Biochemical Journal ◽

10.1042/bj20071382 ◽

2009 ◽

Vol 418 (1) ◽

pp. 81-91 ◽

Cited By ~ 26

Author(s):

Hansruedi Stettler ◽

Nicole Beuret ◽

Cristina Prescianotto-Baschong ◽

Bérengère Fayard ◽

Laurent Taupenot ◽

...

Keyword(s):

Chromogranin A ◽

Endocrine Cells ◽

Secretory Pathway ◽

Fluorescent Protein ◽

Secretory Granules ◽

Peptide Hormone ◽

Secretory Proteins ◽

Cell Periphery ◽

Granule Formation ◽

Regulated Secretory Pathway

In endocrine cells, prohormones and granins are segregated in the TGN (trans-Golgi network) from constitutively secreted proteins, stored in concentrated form in dense-core secretory granules, and released in a regulated manner on specific stimulation. The mechanism of granule formation is only partially understood. Expression of regulated secretory proteins, both peptide hormone precursors and granins, had been found to be sufficient to generate structures that resemble secretory granules in the background of constitutively secreting, non-endocrine cells. To identify which segment of CgA (chromogranin A) is important to induce the formation of such granule-like structures, a series of deletion constructs fused to either GFP (green fluorescent protein) or a short epitope tag was expressed in COS-1 fibroblast cells and analysed by fluorescence and electron microscopy and pulse-chase labelling. Full-length CgA as well as deletion constructs containing the N-terminal 77 residues generated granule-like structures in the cell periphery that co-localized with co-expressed SgII (secretogranin II). These are essentially the same segments of the protein that were previously shown to be required for granule sorting in wild-type PC12 (pheochromocytoma cells) cells and for rescuing a regulated secretory pathway in A35C cells, a variant PC12 line deficient in granule formation. The results support the notion that self-aggregation is at the core of granule formation and sorting into the regulated pathway.

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Prohormone transport through the secretory pathway of neuroendocrine cells

Biochemistry and Cell Biology ◽

10.1139/o00-020 ◽

2000 ◽

Vol 78 (3) ◽

pp. 289-298 ◽

Cited By ~ 12

Author(s):

Roland P Kuiper ◽

Gerard JM Martens

Keyword(s):

Secretory Pathway ◽

Potential Role ◽

Protein Transport ◽

Secretory Granules ◽

Secretory Protein ◽

Neuroendocrine Cells ◽

Secretory Proteins ◽

Regulated Secretory Pathway ◽

Made In

En route through the secretory pathway of neuroendocrine cells, prohormones pass a series of membrane-bounded compartments. During this transport, the prohormones are sorted to secretory granules and proteolytically cleaved to bioactive peptides. Recently, progress has been made in a number of aspects concerning secretory protein transport and sorting, particularly with respect to transport events in the early regions of the secretory pathway. In this review we will deal with some of these aspects, including: i) selective exit from the endoplasmic reticulum via COPII-coated vesicles and the potential role of p24 putative cargo receptors in this process, ii) cisternal maturation as an alternative model for protein transport through the Golgi complex, and iii) the mechanisms that may be involved in the sorting of regulated secretory proteins to secretory granules. Although much remains to be learned, interesting new insights into the functioning of the secretory pathway have been obtained.Key words: regulated secretory pathway, p24 family, vesicular transport, POMC, protein sorting, secretory granule, Xenopus laevis.

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