Biogenesis and Transport of Secretory Granules to Release Site in Neuroendocrine Cells

  • Joshua J. Park
  • Hisatsugu Koshimizu
  • Y. Peng Loh


Biogenesis and post-Golgi transport of peptidergic secretory granules to the release site are crucial for secretion of neuropeptides from neuroendocrine cells. Recent studies have uncovered multilevel molecular mechanisms for the regulation of secretory granule biogenesis. Insulinoma-associated protein 2 (ICA512/IA-2), polypyrimidine-tract binding protein, and chromogranin A have been identified to regulate secretory granule biogenesis at the transcriptional, posttranscriptional, and posttranslational levels, respectively, by increasing granule protein levels, which in turn drives granule formation after stimulation. Post-Golgi transport of secretory granules is microtubule-based and mediated by transmembrane carboxypeptidase E (CPE). The cytoplasmic tail of CPE anchors secretory granules to the microtubule motors, kinesin-2 and -3, or dynein, via interaction with the adaptor, dynactin, to mediate anterograde and retrograde transport, respectively.


Biogenesis of peptidergic secretory granules Chromogranin A Expression of inhibitor of protein Nexin-1 Carboxypeptidase E or cytoplasmic tail Post-Golgi transport Dynactin Microtubule-based motors 


  1. Alexander, K., Nikodemova, M., Kucerova, J., & Strbak, V. (2005). Colchicine treatment differently affects releasable thyrotropin-releasing hormone (TRH) pools in the hypothalamic paraventricular nucleus (PVN) and the median eminence (ME). Cellular and Molecular Neurobiology, 25, 681–695, doi:10.1007/s10571-005-4008-0.PubMedCrossRefGoogle Scholar
  2. Auweter, S. D., & Allain, F. H. (2007). Structure–function relationships of the polypyrimidine tract binding protein. Cellular and Molecular Life Science, 65, 516–527.CrossRefGoogle Scholar
  3. Bennett, H. S. (1941). Cytological manifestations of secretion in the adrenal medulla of the cat. The American Journal of Anatomy, 69, 333–381. doi:10.1002/aja.1000690302.CrossRefGoogle Scholar
  4. Beuret, N., Stettler, H., Renold, A., Rutishauser, J., & Spiess, M. (2004). Expression of regulated secretory proteins is sufficient to generate granule-like structures in constitutively secreting cells. The Journal of Biological Chemistry, 279, 20242–20249, doi:10.1074/jbc.M310613200.PubMedCrossRefGoogle Scholar
  5. Berezuk, M. A., & Schroer, T. A. (2007). Dynactin enhances the processivity of kinesin-2. Traffic, 8, 124–129, doi:10.1111/j.1600-0854.2006.00517.x.PubMedCrossRefGoogle Scholar
  6. Blaschko, H., Comline, R. S., Schneider, F. H., Silver, M., & Smith, A. D. (1967). Secretion of a chromaffin granule protein, chromogranin, from the adrenal gland after splanchnic stimulation. Nature, 215, 58–59, doi:10.1038/215058a0.PubMedCrossRefGoogle Scholar
  7. Bruce, A. W., Donaldson, I. J., Wood, I. C., Yerbury, S. A., Sadowski, M. I., Chapman, M., et al. (2004). Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. Proceedings of National Academy of Science U S A, 101, 10458–10463, doi:10.1073/pnas.0401827101.CrossRefGoogle Scholar
  8. Bruce, A. W., KreJci, A., Ooi, L., Wood, I. C., Dolezal, V., & Buckley, N. J. (2006). The transcriptional repressor REST is a critical regulator of the neurosecretory phenotype. Journal of Neurochemistry, 98, 1828–1840, doi:10.1111/j.1471-4159.2006.04010.x.PubMedCrossRefGoogle Scholar
  9. Calderone, A., Jover, T., Noh, K. M., Tanaka, H., Yokota, H., Lin, Y., et al. (2003). Ischemic insults derepress the gene silencer REST in neurons destined to die. The Journal of Neuroscience, 23, 2112–2121.PubMedGoogle Scholar
  10. Chong, J. A., Tapia-Ramirez, J., Kim, S., Toledo-Aral, J. J., Zheng, Y., Boutros, M. C., et al. (1995). RESY: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell, 80, 949–957, doi:10.1016/0092-8674(95)90298-8.PubMedCrossRefGoogle Scholar
  11. Cool, D. R., Normant, E., Shen, F., Chen, H. C., Pannell, L., Zhang, Y., & Loh, Y. P. (1997). Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cell, 88, 73–83, doi:10.1016/S0092-8674(00)81860-7.PubMedCrossRefGoogle Scholar
  12. Eaton, B. A., Haugwitz, M., Lau, D., & Moore, H. P. (2000). Biogenesis of regulated exocytotic carriers in neuroendocrine cells. Journal of Neuroscience, 20, 7334–7344.PubMedGoogle Scholar
  13. Eiden, L. E., Giraud, P., Dave, J. R., Hotchkiss, A. J., & Affolter, H. U. (1984). Nicotinic receptor stimulation activates enkephalin release and biosynthesis in adrenal chromaffin cells. Nature, 312, 661–663, doi:10.1038/312661a0.PubMedCrossRefGoogle Scholar
  14. Dikeakos, J. D., & Reudelhuber, T. L. (2007). Sending proteins to dense core secretory granules: still a lot to sort out. The Journal of Cell Biology, 177, 191–196, doi:10.1083/jcb.200701024.PubMedCrossRefGoogle Scholar
  15. Gauthier, L. R., Charrin, B. C., Borrell-Pages, M., Dompierre, J. P., Rangone, H., Cordelieres, F. P., et al. (2004). Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell, 118, 127–138, doi:10.1016/j.cell.2004.06.018.PubMedCrossRefGoogle Scholar
  16. Gill, S. R., Schroer, T. A., Szilak, I., Steuer, E. R., Sheetz, M. P., & Cleveland, D. W. (1991). Dynactin, a conserved, ubiquitously expressed component of an activator of vesicle motility mediated by cytoplasmic dynein. Journal of Cell Biology, 115, 1639–1650, doi:10.1083/jcb.115.6.1639.PubMedCrossRefGoogle Scholar
  17. Grundschober, C., Malosio, M. L., Astolfi, L., Giordano, T., Nef, P., & Meldolesi, J. (2002). Neurosecretion competence. A comprehensive gene expression program identified in PC12 cells. Journal of Biological Chemistry, 277, 36715–36724 Erratum in: (2002). Journal of Biological Chemistry, 277, 46840. doi:10.1074/jbc.M203777200.PubMedCrossRefGoogle Scholar
  18. Hamm-Alvarez, S. F., Da Costa, S., Yang, T., Wei, X., Gierow, J. P., & Mircheff, A. K. (1997). Cholinergic stimulation of lacrimal acinar cells promotes redistribution of membrane-associated kinesin and the secretory protein, beta-hexosaminidase, and increases kinesin motor activity. Experimental Eye Research, 64, 141–156, doi:10.1006/exer.1996.0198.PubMedCrossRefGoogle Scholar
  19. Harashima, S., Clark, A., Christie, M. R., & Notkins, A. L. (2005). The dense core transmembrane vesicle protein IA-2 is a regulator of vesicle number and insulin secretion. Proceedings of National Academy of Science U S A, 102, 8704–8709, doi:10.1073/pnas.0408887102.CrossRefGoogle Scholar
  20. Hiremagalur, B., Nankova, B., Nitahara, J., Zeman, R., & Sabban, E. L. (1993). Nicotine increases expression of tyrosine hydroxylase gene. Involvement of protein kinase A-mediated pathway. The Journal of Biological Chemistry, 268, 23704–23711.PubMedGoogle Scholar
  21. Huh, Y. H., Jeon, S. H., & Yoo, S. H. (2003). Chromogranin B-induced secretory granule biogenesis: comparison with the similar role of chromogranin. Journal of Biological Chemistry, 278, 40581–40589. doi:10.1074/jbc.M304942200.PubMedCrossRefGoogle Scholar
  22. Hendy, G. N., Li, T., Girard, M., Feldstein, R. C., Mulay, S., Desjardins, R., et al. (2006). Targeted ablation of the chromogranin a (Chga) gene: normal neuroendocrine dense-core secretory granules and increased expression of other granins. Molecular Endocrinology, 20, 1935–1947, doi:10.1210/me.2005-0398.PubMedCrossRefGoogle Scholar
  23. 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. Molecular Biology of Cell, 13, 3388–3399, doi:10.1091/mbc.02-03-0040.CrossRefGoogle Scholar
  24. Jacob, T. C., & Kaplan, J. M. (2003). The EGL-21 carboxypeptidase E facilitates acetylcholine release at Caenorhabditis elegans neuromuscular junctions. Journal of Neuroscience, 23, 2122–2130.PubMedGoogle Scholar
  25. Kalinina, E., Varlamov, O., & Fricker, L. D. (2002). Analysis of the carboxypeptidase D cytoplasmic domain: Implications in intracellular trafficking. Journal of Cellular Biochemistry, 85, 101–111, doi:10.1002/jcb.10112.PubMedCrossRefGoogle Scholar
  26. Kilbourne, E. J., Nankova, B. B., Lewis, E. J., McMahon, A., Osaka, H., Sabban, D. B., et al. (1992). Regulated expression of the tyrosine hydroxylase gene by membrane depolarization. Identification of the responsive element and possible second messengers. The Journal of Biological Chemistry, 267, 7563–7569.PubMedGoogle Scholar
  27. Kim, T., Gondre-Lewis, M. C., Arnauotova, I., & Loh, Y. P. (2006). Dense-core secretory granule biogenesis. Physiology (Bethesda), 21, 24–33. doi:10.1152/physiol.00043.2005.Google Scholar
  28. Kim, T., & Loh, Y. P. (2006). Protein nexin-1 promotes secretory granule biogenesis by preventing granule protein degradation. Molecular Biology of the Cell, 2, 789–798.Google Scholar
  29. Kim, T., Tao-Cheng, J. H., Eiden, L. E., & Loh, Y. P. (2001). Chromogranin A, an “on/off” switch controlling dense-core secretory granule biogenesis. Cell, 106, 499–509, doi:10.1016/S0092-8674(01)00459-7.PubMedCrossRefGoogle Scholar
  30. Knoch, K. P., Bergert, H., Borgonovo, B., Saeger, H. D., Altkruger, A., Verkade, P., et al. (2004). Polypyrimidine tract-binding protein promotes insulin secretory granule biogenesis. Nature Cell Biology, 6, 207–214, doi:10.1038/ncb1099.PubMedCrossRefGoogle Scholar
  31. Kondo, S., Sato-Yoshitake, R., Noda, Y., Aizawa, H., Nakata, T., Matsuura, Y., et al. (1994). KIF3A is a new microtubule-based anterograde motor in the nerve axon. Journal of Cell Biology, 125, 1095–1107, doi:10.1083/jcb.125.5.1095.PubMedCrossRefGoogle Scholar
  32. Loh, Y. P., Maldonado, A., Zhang, C., Tam, W. H., & Cawley, N. (2002). Mechanism of sorting proopiomelanocortin and proenkaphalin to the regulated secretory pathway of neuroendocrine cells. ANNALS of the New York Academy of Sciences, 971, 416–425.PubMedGoogle Scholar
  33. Mahapatra, N. R., Mahata, M., O’Connor, D. T., & Mahata, S. K. (2003). Secretin activation of chromogranin A gene transcription. Identification of the signaling pathways in cis and in trans. The Journal of Biological Chemistry, 278, 19986–19994, doi:10.1074/jbc.M207983200.PubMedCrossRefGoogle Scholar
  34. Mahapatra, N. R., O’Connor, D. T., Vaingankar, S. M., HiKim, A. P., Mahata, M., Ray, S., et al. (2005). Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. The Journal of Clinical Investigation, 115, 1942–1952, doi:10.1172/JCI24354.PubMedCrossRefGoogle Scholar
  35. Malosio, M. L., Giordano, T., Laslop, A., & Meldolesi, J. (2004). Dense-core granules: a specific hallmark of the neuronal/neurosecretory cell phenotype. Journal of Cell Science, 117, 743–749, doi:10.1242/jcs.00934.PubMedCrossRefGoogle Scholar
  36. Palm, K., Belluardo, N., Metsis, M., & Timmusk, T. (1998). Neuronal expression of zinc finger transcription factor REST/NRSF/XBR gene. Journal of Neuroscience, 18, 1280–1296.PubMedGoogle Scholar
  37. Pance, A., Livesey, F. J., & Jackson, A. P. (2006). A role for the transcriptional repressor REST in maintaining the phenotype of neurosecretory-deficient PC12 cells. Journal of Neurochemistry, 99, 1435–1444, doi:10.1111/j.1471-4159.2006.04190.x.PubMedCrossRefGoogle Scholar
  38. Park, J. J., Cawley, N. X., & Loh, Y. P. (2008). Carboxypeptidase E cytoplasmic tail-driven vesicle transport is key for activity-dependent secretion of peptide hormones. Molecular Endocrinology, 22, 989–1005.PubMedCrossRefGoogle Scholar
  39. Rausch, D. M., Iacangelo, A. L., & Eiden, L. E. (1988). Glucocorticoid-and nerve growth factor-induced changes in chromogranin A expression define two different neuronal phenotypes in PC12 cells. Molecular Endocrinology, 2, 921–927.PubMedCrossRefGoogle Scholar
  40. Rudolf, R., Salm, T., Rustom, A., & Gerdes, H. H. (2001). Dynamics of immature secretory granules: role of cytoskeletal elements during transport, cortical restriction, and F-actin-dependent tethering. Molecular Biology of Cell, 12, 1353–1365.Google Scholar
  41. Schoenherr, C. J., & Anderson, D. J. (1995). Silencing is golden: negative regulation in the control of neuronal gene transcription. Current Opinion in Neurobiology, 5, 566–571, doi:10.1016/0959-4388(95)80060-3.PubMedCrossRefGoogle Scholar
  42. Senda, T., & Yu, W. (1999). Kinesin cross-bridges between neurosecretory granules and microtubules in the mouse neurohypophysis. Neuroscience Letter, 262, 69–71, doi:10.1016/S0304-3940(99)00042-7.CrossRefGoogle Scholar
  43. Shakiryanova, D., Tully, A., & Levitan, E. S. (2006). Activity-dependent synaptic capture of transiting peptidergic vesicles. Nature Neuroscience, 9, 896–900, doi:10.1038/nn1719.PubMedCrossRefGoogle Scholar
  44. Tang, K., Wu, H., Mahata, S. K., Taupenot, L., Rozansky, D. J., Parmer, R. J., et al. (1996). Stimulus-transcription coupling in pheochromocytoma cells. Promoter region-specific activation of chromogranin a biosynthesis. The Journal of Biological Chemistry, 271, 28382–28390, doi:10.1074/jbc.271.45.28382.PubMedCrossRefGoogle Scholar
  45. Trajkovski, M., Mziaut, H., Altkruger, A., Ouwendijk, J., Knoch, K. P., Muller, S., et al. (2004). Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in beta-cells. The Journal of Cell Biology, 167, 1063–1074, doi:10.1083/jcb.200408172.PubMedCrossRefGoogle Scholar
  46. Varadi, A., Tsuboi, T., Johnson-Cadwell, L. I., Allan, V. J., & Rutter, G. A. (2003). Kinesin I and cytoplasmic dynein orchestrate glucose-stimulated insulin-containing vesicle movements in clonal MIN6 beta-cells. Biochemical and Biophysical Research Communications, 311, 272–282, doi:10.1016/j.bbrc.2003.09.208.PubMedCrossRefGoogle Scholar
  47. Varlamov, O., Kalinina, E., Chen, F. Y., & Fricker, L. D. (2001). Protein phosphatase 2A binds to the cytoplasmic tail of carboxypeptidase D and regulates post-trans-Golgi network trafficking. Journal of Cell Science, 114, 311–322.PubMedGoogle Scholar
  48. Yamazaki, H., Nakata, T., Okada, Y., & Hirokawa, N. (1995). KIF3A/B: a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport. Journal of Cell Biology, 130, 1387–1399, doi:10.1083/jcb.130.6.1387.PubMedCrossRefGoogle Scholar
  49. Yamazaki, H., Nakata, T., Okada, Y., & Hirokawa, N. (1996). Cloning and characterization of KAP3: a novel kinesin superfamily-associated protein of KIF3A/3B. Proceedings of National Academy of Science U S A, 93, 8443–8448, doi:10.1073/pnas.93.16.8443.CrossRefGoogle Scholar

Copyright information

© Humana Press 2008

Authors and Affiliations

  • Joshua J. Park
    • 1
  • Hisatsugu Koshimizu
    • 1
  • Y. Peng Loh
    • 1
  1. 1.Section on Cellular Neurobiology, Developmental Neurobiology Program, National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaUSA

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