Chromogranins as Molecular Coordinators at the Crossroads between Hormone Aggregation and Secretory Granule Biogenesis

  • O. Carmon
  • F. Laguerre
  • L. Jeandel
  • Y. AnouarEmail author
  • M. Montero-Hadjadje
Part of the UNIPA Springer Series book series (USS)


Chromogranins are members of a family of soluble glycoproteins sharing common structural features and properties, known to be inducers of prohormone aggregation and sorting into secretory granules. There is now increasing evidence for a key role of chromogranins in hormone sorting to the regulated secretory pathway, resulting from the interaction of chromogranin-induced aggregates with the TGN membrane through either sorting receptors such as carboxypeptidase E, or lipids such as cholesterol. These molecular interactions would contribute to the TGN membrane remodeling, a prerequisite to the recruitment of cytosolic proteins inducing membrane curvature and consecutive secretory granule budding. The identification of the molecular cues involved in the biogenesis of secretory granules is currently under intense investigation. The diversity of chromogranins sharing common structural features but with possible non-redundant functions implies a variety of secretory granule populations whose existence and function remain to be established in a given neuroendocrine cell type.

The present chapter deals with the role of the different members of the chromogranin family in the processes of hormone aggregation, secretory granule biogenesis, and hormone sorting through their interaction with the TGN membrane. Finally, the alteration of chromogranin secretion is described in pathophysiological conditions linked to dysregulated hormone secretion.


Chromogranin A Chromogranin B Secretogranin II Secretogranin III VEGF Trans-Golgi network Secretory granules Sorting receptors Endomembranes 


  1. Bandyopadhyay GK, Vu CU, Gentile S, Lee H, Biswas N, Chi N-W, O’Connor DT, Mahata SK (2012) Catestatin (chromogranin A(352-372)) and novel effects on mobilization of fat from adipose tissue through regulation of adrenergic and leptin signaling. J Biol Chem 287:23141–23151CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bartolomucci A, Possenti R, Mahata SK, Fischer-Colbrie R, Loh YP, Salton SRJ (2011) The extended granin family: structure, function, and biomedical implications. Endocr Rev 32:755–797CrossRefPubMedPubMedCentralGoogle Scholar
  3. Cawley NX, Rathod T, Young S, Lou H, Birch N, Loh YP (2016) Carboxypeptidase E and secretogranin III coordinately facilitate efficient sorting of proopiomelanocortin to the regulated secretory pathway in AtT20 cells. Mol Endocrinol 30:37–47CrossRefPubMedGoogle Scholar
  4. Chanat E, Huttner WB (1991) Milieu-induced, selective aggregation of regulated secretory proteins in the trans-Golgi network. J Cell Biol 115:1505–1519CrossRefPubMedGoogle Scholar
  5. Chen Y, Rao F, Rodriguez-Flores JL et al (2008) Naturally occurring human genetic variation in the 3′-untranslated region of the secretory protein chromogranin A is associated with autonomic blood pressure regulation and hypertension in a sex-dependent fashion. J Am Coll Cardiol 52:1468–1481CrossRefPubMedPubMedCentralGoogle Scholar
  6. Colombo B, Curnis F, Foglieni C, Monno A, Arrigoni G, Corti A (2002) Chromogranin A expression in neoplastic cells affects tumor growth and morphogenesis in mouse models. Cancer Res 62:941–946PubMedGoogle Scholar
  7. Courel M, Soler-Jover A, Rodriguez-Flores JL, Mahata SK, Elias S, Montero-Hadjadje M, Anouar Y, Giuly RJ, O’Connor DT, Taupenot L (2010) Pro-hormone secretogranin II regulates dense core secretory granule biogenesis in catecholaminergic cells. J Biol Chem 285:10030–10043CrossRefPubMedPubMedCentralGoogle Scholar
  8. Courel M, El Yamani F-Z, Alexandre D et al (2014) Secretogranin II is overexpressed in advanced prostate cancer and promotes the neuroendocrine differentiation of prostate cancer cells. Eur J Cancer 50:3039–3049CrossRefPubMedGoogle Scholar
  9. Cowley DJ, Moore YR, Darling DS, Joyce PB, Gorr SU (2000) N- and C-terminal domains direct cell type-specific sorting of chromogranin A to secretory granules. J Biol Chem 275:7743–7748CrossRefPubMedGoogle Scholar
  10. Cruz-Garcia D, Ortega-Bellido M, Scarpa M, Villeneuve J, Jovic M, Porzner M, Balla T, Seufferlein T, Malhotra V (2013) Recruitment of arfaptins to the trans-Golgi network by PI(4)P and their involvement in cargo export. EMBO J 32:1717–1729CrossRefPubMedPubMedCentralGoogle Scholar
  11. Dannies PS (2001) Concentrating hormones into secretory granules: layers of control. Mol Cell Endocrinol 177:87–93CrossRefPubMedGoogle Scholar
  12. Díaz-Vera J, Morales YG, Hernández-Fernaud JR, Camacho M, Montesinos MS, Calegari F, Huttner WB, Borges R, Machado JD (2010) Chromogranin B gene ablation reduces the catecholamine cargo and decelerates exocytosis in chromaffin secretory vesicles. J Neurosci 30:950–957CrossRefPubMedGoogle Scholar
  13. Dikeakos JD, Reudelhuber TL (2007) Sending proteins to dense core secretory granules: still a lot to sort out: Figure 1. J Cell Biol 177(2):191–196Google Scholar
  14. Elias S, Delestre C, Ory S, Marais S, Courel M, Vazquez-Martinez R, Bernard S, Coquet L, Malagon MM, Driouich A, Chan P, Gasman S, Anouar Y, Montero-Hadjadje M (2012) Chromogranin A Induces the Biogenesis of Granules with Calcium- and Actin-Dependent Dynamics and Exocytosis in Constitutively Secreting Cells. Endocrinol 153(9):4444–4456Google Scholar
  15. Fargali S, Garcia AL, Sadahiro M et al (2014) The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure. FASEB J 28:2120–2133CrossRefPubMedPubMedCentralGoogle Scholar
  16. Frost A, Unger VM, De Camilli P (2009) The BAR domain superfamily: membrane-molding macromolecules. Cell 137:191–196CrossRefPubMedPubMedCentralGoogle Scholar
  17. Gehart H, Goginashvili A, Beck R, Morvan J, Erbs E, Formentini I, De Matteis MA, Schwab Y, Wieland FT, Ricci R (2012) The BAR domain protein Arfaptin-1 controls secretory granule biogenesis at the trans-Golgi network. Dev Cell 23:756–768CrossRefPubMedGoogle Scholar
  18. Gondré-Lewis MC, Park JJ, Loh YP (2012) Cellular mechanisms for the biogenesis and transport of synaptic and dense-core vesicles. Int Rev Cell Mol Biol 299:27–115CrossRefPubMedGoogle Scholar
  19. Guérin M, Guillemot J, Thouënnon E et al (2010) Granins and their derived peptides in normal and tumoral chromaffin tissue: implications for the diagnosis and prognosis of pheochromocytoma. Regul Pept 165:21–29CrossRefPubMedGoogle Scholar
  20. Guillemot J, Anouar Y, Montero-Hadjadje M et al (2006) Circulating EM66 is a highly sensitive marker for the diagnosis and follow-up of pheochromocytoma. Int J Cancer 118:2003–2012CrossRefPubMedGoogle Scholar
  21. Guillemot J, Guérin M, Thouënnon E, Montéro-Hadjadje M, Leprince J, Lefebvre H, Klein M, Muresan M, Anouar Y, Yon L (2014) Characterization and plasma measurement of the WE-14 peptide in patients with pheochromocytoma. PLoS One 9:e88698CrossRefPubMedPubMedCentralGoogle Scholar
  22. Haissaguerre M, Courel M, Caron P et al (2013) Normotensive incidentally discovered pheochromocytomas display specific biochemical, cellular, and molecular characteristics. J Clin Endocrinol Metab 98:4346–4354CrossRefPubMedGoogle Scholar
  23. Hendy GN, Li T, Girard M, Feldstein RC, Mulay S, Desjardins R, Day R, Karaplis AC, Tremblay ML, Canaff L (2006) Targeted ablation of the chromogranin a (Chga) gene: normal neuroendocrine dense-core secretory granules and increased expression of other granins. Mol Endocrinol 20:1935–1947CrossRefPubMedGoogle Scholar
  24. Holst B, Madsen KL, Jansen AM et al (2013) PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance. PLoS Biol 11:e1001542CrossRefPubMedPubMedCentralGoogle Scholar
  25. Hosaka M, Watanabe T, Sakai Y, Uchiyama Y, Takeuchi T (2002) Identification of a chromogranin A domain that mediates binding to secretogranin III and targeting to secretory granules in pituitary cells and pancreatic beta-cells. Mol Biol Cell 13:3388–3399CrossRefPubMedPubMedCentralGoogle Scholar
  26. Hosaka M, Suda M, Sakai Y, Izumi T, Watanabe T, Takeuchi T (2004) Secretogranin III binds to cholesterol in the secretory granule membrane as an adapter for chromogranin A. J Biol Chem 279:3627–3634CrossRefPubMedGoogle Scholar
  27. Hosaka M, Watanabe T, Sakai Y, Kato T, Takeuchi T (2005) Interaction between secretogranin III and carboxypeptidase E facilitates prohormone sorting within secretory granules. J Cell Sci 118:4785–4795CrossRefPubMedGoogle Scholar
  28. Kim T, Tao-Cheng JH, Eiden LE, Loh YP (2001) Chromogranin A, an “on/off” switch controlling dense-core secretory granule biogenesis. Cell 106:499–509CrossRefPubMedGoogle Scholar
  29. Kim T, Gondré-Lewis MC, Arnaoutova I, Loh YP (2006) Dense-core secretory granule biogenesis. Physiology (Bethesda) 21:124–133CrossRefGoogle Scholar
  30. Kingsley DM, Rinchik EM, Russell LB, Ottiger HP, Sutcliffe JG, Copeland NG, Jenkins NA (1990) Genetic ablation of a mouse gene expressed specifically in brain. EMBO J 9:395–399PubMedPubMedCentralGoogle Scholar
  31. Machado JD, Díaz-Vera J, Domínguez N, Alvarez CM, Pardo MR, Borges R (2010) Chromogranins A and B as regulators of vesicle cargo and exocytosis. Cell Mol Neurobiol 30:1181–1187CrossRefPubMedGoogle Scholar
  32. Mahapatra NR, O’Connor DT, Vaingankar SM et al (2005) Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest 115:1942–1952CrossRefPubMedPubMedCentralGoogle Scholar
  33. Mahapatra NR, Taupenot L, Courel M, Mahata SK, O’Connor DT (2008) The trans-Golgi proteins SCLIP and SCG10 interact with chromogranin A to regulate neuroendocrine secretion. Biochemistry 47:7167–7178CrossRefPubMedPubMedCentralGoogle Scholar
  34. Mazzawi T, El-Salhy M (2016) Changes in small intestinal chromogranin A-immunoreactive cell densities in patients with irritable bowel syndrome after receiving dietary guidance. Int J Mol Med 37:1247–1253CrossRefPubMedPubMedCentralGoogle Scholar
  35. Metz-Boutigue MH, Garcia-Sablone P, Hogue-Angeletti R, Aunis D (1993) Intracellular and extracellular processing of chromogranin A. Determination of cleavage sites. Eur J Biochem 217:247–257CrossRefPubMedGoogle Scholar
  36. Montero-Hadjadje M, Vaingankar S, Elias S, Tostivint H, Mahata SK, Anouar Y (2008) Chromogranins A and B and secretogranin II: evolutionary and functional aspects. Acta Physiol (Oxf) 192:309–324CrossRefGoogle Scholar
  37. Moran GW, Pennock J, McLaughlin JT (2012) Enteroendocrine cells in terminal ileal Crohn’s disease. J Crohns Colitis 6:871–880CrossRefPubMedGoogle Scholar
  38. Mosley CA, Taupenot L, Biswas N et al (2007) Biogenesis of the secretory granule: chromogranin A coiled-coil structure results in unusual physical properties and suggests a mechanism for granule core condensation. Biochemistry 46:10999–11012CrossRefPubMedGoogle Scholar
  39. O’Connor DT, Bernstein KN (1984) Radioimmunoassay of chromogranin A in plasma as a measure of exocytotic sympathoadrenal activity in normal subjects and patients with pheochromocytoma. N Engl J Med 311:764–770CrossRefPubMedGoogle Scholar
  40. Obermüller S, Calegari F, King A et al (2010) Defective secretion of islet hormones in chromogranin-B deficient mice. PLoS One 5:e8936CrossRefPubMedPubMedCentralGoogle Scholar
  41. Pinheiro PS, Jansen AM, de Wit H, Tawfik B, Madsen KL, Verhage M, Gether U, Sørensen JB (2014) The BAR domain protein PICK1 controls vesicle number and size in adrenal chromaffin cells. J Neurosci 34:10688–10700CrossRefPubMedPubMedCentralGoogle Scholar
  42. Rao Y, Haucke V (2011) Membrane shaping by the Bin/amphiphysin/Rvs (BAR) domain protein superfamily. Cell Mol Life Sci 68:3983–3993CrossRefPubMedGoogle Scholar
  43. Rao F, Wen G, Gayen JR et al (2007) Catecholamine release-inhibitory peptide catestatin (chromogranin A(352-372)): naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension. Circulation 115:2271–2281CrossRefPubMedGoogle Scholar
  44. Sun M, Watanabe T, Bochimoto H, Sakai Y, Torii S, Takeuchi T, Hosaka M (2013) Multiple sorting systems for secretory granules ensure the regulated secretion of peptide hormones. Traffic 14:205–218CrossRefPubMedGoogle Scholar
  45. Takiyyuddin MA, Brown MR, Dinh TQ, Cervenka JH, Braun SD, Parmer RJ, Kennedy B, O’Connor DT (1994) Sympatho-adrenal secretion in humans: factors governing catecholamine and storage vesicle peptide co-release. J Auton Pharmacol 14:187–200CrossRefPubMedGoogle Scholar
  46. Taupenot L, Harper KL, O’Connor DT (2003) The chromogranin-secretogranin family. N Engl J Med 348:1134–1149CrossRefPubMedGoogle Scholar
  47. Thiele C, Huttner WB (1998) The disulfide-bonded loop of chromogranins, which is essential for sorting to secretory granules, mediates homodimerization. J Biol Chem 273:1223–1231CrossRefPubMedGoogle Scholar
  48. Yon L, Guillemot J, Montero-Hadjadje M, Grumolato L, Leprince J, Lefebvre H, Contesse V, Plouin P-F, Vaudry H, Anouar Y (2003) Identification of the secretogranin II-derived peptide EM66 in pheochromocytomas as a potential marker for discriminating benign versus malignant tumors. J Clin Endocrinol Metab 88:2579–2585CrossRefPubMedGoogle Scholar
  49. Yoo SH, Lewis MS (1993) Dimerization and tetramerization properties of the C-terminal region of chromogranin A: a thermodynamic analysis. Biochemistry 32:8816–8822CrossRefPubMedGoogle Scholar
  50. Zhang D, Lavaux T, Voegeli AC, Lavigne T, Castelain V, Meyer N, Sapin R, Aunis D, Metz-Boutigue MH, Schneider F (2008) Prognostic value of chromogranin A at admission in critically ill patients: a cohort study in a medical intensive care unit. Clin Chem 54:1497–1503CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • O. Carmon
    • 1
  • F. Laguerre
    • 1
  • L. Jeandel
    • 1
  • Y. Anouar
    • 1
    Email author
  • M. Montero-Hadjadje
    • 1
  1. 1.Institute for Research and Innovation in BiomedicineInserm U1239, University of Rouen-Normandy, UNIROUENMont-Saint-AignanFrance

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