Protein & Cell

, Volume 3, Issue 8, pp 618–626 | Cite as

Bulk-like endocytosis plays an important role in the recycling of insulin granules in pancreatic beta cells

  • Du Wen
  • Yanhong Xue
  • Kuo Liang
  • Tianyi Yuan
  • Jingze Lu
  • Wei Zhao
  • Tao XuEmail author
  • Liangyi ChenEmail author
Research Article


Although bulk endocytosis has been found in a number of neuronal and endocrine cells, the molecular mechanism and physiological function of bulk endocytosis remain elusive. In pancreatic beta cells, we have observed bulk-like endocytosis evoked both by flash photolysis and trains of depolarization. Bulk-like endocytosis is a clathrin-independent process that is facilitated by enhanced extracellular Ca2+ entry and suppressed by the inhibition of dynamin function. Moreover, defects in bulk-like endocytosis are accompanied by hyperinsulinemia in primary beta cells dissociated from diabetic KKAy mice, which suggests that bulk-like endocytosis plays an important role in maintaining the exo-endocytosis balance and beta cell secretory capability.


bulk-like endocytosis clathrin-independent endocytosis dynamin diabetic KKAy mice 


  1. Anggono, V., Smillie, K.J., Graham, M.E., Valova, V.A., Cousin, M.A., and Robinson, P.J. (2006). Syndapin I is the phosphorylation-regulated dynamin I partner in synaptic vesicle endocytosis. Nat Neurosci 9, 752–760.CrossRefGoogle Scholar
  2. Cao, H., Garcia, F., and McNiven, M.A. (1998). Differential distribution of dynamin isoforms in mammalian cells. Mol Biol Cell 9, 2595–2609.CrossRefGoogle Scholar
  3. Clayton, E.L., Anggono, V., Smillie, K.J., Chau, N., Robinson, P.J., and Cousin, M.A. (2009). The phospho-dependent dynamin-syndapin interaction triggers activity-dependent bulk endocytosis of synaptic vesicles. J Neurosci 29, 7706–7717.CrossRefGoogle Scholar
  4. Clayton, E.L., and Cousin, M.A. (2009). The molecular physiology of activity-dependent bulk endocytosis of synaptic vesicles. J Neurochem 111, 901–914.CrossRefGoogle Scholar
  5. Clayton, E.L., Evans, G.J., and Cousin, M.A. (2008). Bulk synaptic vesicle endocytosis is rapidly triggered during strong stimulation. J Neurosci 28, 6627–6632.CrossRefGoogle Scholar
  6. Clayton, E.L., Sue, N., Smillie, K.J., O’Leary, T., Bache, N., Cheung, G., Cole, A.R., Wyllie, D.J., Sutherland, C., Robinson, P.J., et al. (2010). Dynamin I phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles. Nat Neurosci 13, 845–851.CrossRefGoogle Scholar
  7. Duman, J.G., Chen, L., Palmer, A.E., and Hille, B. (2006). Contributions of intracellular compartments to calcium dynamics: implicating an acidic store. Traffic 7, 859–872.CrossRefGoogle Scholar
  8. Eliasson, L., Abdulkader, F., Braun, M., Galvanovskis, J., Hoppa, M.B., and Rorsman, P. (2008). Novel aspects of the molecular mechanisms controlling insulin secretion. J Physiol 586, 3313–3324.CrossRefGoogle Scholar
  9. Eliasson, L., Proks, P., Ammala, C., Ashcroft, F.M., Bokvist, K., Renstrom, E., Rorsman, P., and Smith, P.A. (1996). Endocytosis of secretory granules in mouse pancreatic beta-cells evoked by transient elevation of cytosolic calcium. J Physiol 493( Pt 3), 755–767.CrossRefGoogle Scholar
  10. Hayashi, M., Raimondi, A., O’Toole, E., Paradise, S., Collesi, C., Cremona, O., Ferguson, S.M., and De Camilli, P. (2008). Cell- and stimulus-ependent heterogeneity of synaptic vesicle endocytic recycling mechanisms revealed by studies of dynamin 1-null neurons. Proc Natl Acad Sci U S A 105, 2175–2180.CrossRefGoogle Scholar
  11. He, Z., Fan, J., Kang, L., Lu, J., Xue, Y., Xu, P., Xu, T., and Chen, L. (2008). Ca2+ triggers a novel clathrin-independent but actin-dependent fast endocytosis in pancreatic beta cells. Traffic 9, 910–923.CrossRefGoogle Scholar
  12. Heerssen, H., Fetter, R.D., and Davis, G.W. (2008). Clathrin dependence of synaptic-vesicle formation at the Drosophila neuromuscular junction. Curr Biol 18, 401–409.CrossRefGoogle Scholar
  13. Homo-Delarche, F. (1997). Beta-cell behaviour during the prediabetic stage. Part II. Non-insulin-dependent and insulin-dependent diabetes mellitus. Diabetes Metab 23, 473–505.Google Scholar
  14. Hoppa, M.B., Jones, E., Karanauskaite, J., Ramracheya, R., Braun, M., Collins, S.C., Zhang, Q., Clark, A., Eliasson, L., Genoud, C., et al. (2012). Multivesicular exocytosis in rat pancreatic beta cells. Diabetologia 55, 1001–1012.CrossRefGoogle Scholar
  15. Kwan, E.P., and Gaisano, H.Y. (2005). Glucagon-like peptide 1 regulates sequential and compound exocytosis in pancreatic islet beta-cells. Diabetes 54, 2734–2743.CrossRefGoogle Scholar
  16. Lee, A.K., and Tse, A. (2001). Endocytosis in identified rat corticotrophs. J Physiol 533, 389–405.CrossRefGoogle Scholar
  17. Lenzi, D., Crum, J., Ellisman, M.H., and Roberts, W.M. (2002). Depolarization redistributes synaptic membrane and creates a gradient of vesicles on the synaptic body at a ribbon synapse. Neuron 36, 649–659.CrossRefGoogle Scholar
  18. Liang, K., Du, W., Zhu, W., Liu, S., Cui, Y., Sun, H., Luo, B., Xue, Y., Yang, L., Chen, L., et al. (2011). Contribution of different mechanisms to pancreatic beta-cell hyper-secretion in non-obese diabetic (NOD) mice during pre-diabetes. J Biol Chem 286, 39537–39545.CrossRefGoogle Scholar
  19. MacDonald, P.E., Braun, M., Galvanovskis, J., and Rorsman, P. (2006). Release of small transmitters through kiss-and-run fusion pores in rat pancreatic beta cells. Cell Metab 4, 283–290.CrossRefGoogle Scholar
  20. Macia, E., Ehrlich, M., Massol, R., Boucrot, E., Brunner, C., and Kirchhausen, T. (2006). Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell 10, 839–850.CrossRefGoogle Scholar
  21. Newton, A.J., Kirchhausen, T., and Murthy, V.N. (2006). Inhibition of dynamin completely blocks compensatory synaptic vesicle endocytosis. Proc Natl Acad Sci U S A 103, 17955–17960.CrossRefGoogle Scholar
  22. Orci, L., Malaisse-Lagae, F., Ravazzola, M., Amherdt, M., and Renold, A.E. (1973). Exocytosis-endocytosis coupling in the pancreatic beta cell. Science 181, 561–562.CrossRefGoogle Scholar
  23. Ostenson, C.G., Gaisano, H., Sheu, L., Tibell, A., and Bartfai, T. (2006). Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients. Diabetes 55, 435–440.CrossRefGoogle Scholar
  24. Paillart, C., Li, J., Matthews, G., and Sterling, P. (2003). Endocytosis and vesicle recycling at a ribbon synapse. J Neurosci 23, 4092–4099.Google Scholar
  25. Richards, D.A., Guatimosim, C., and Betz, W.J. (2000). Two endocytic recycling routes selectively fill two vesicle pools in frog motor nerve terminals. Neuron 27, 551–559.CrossRefGoogle Scholar
  26. Rorsman, P., and Trube, G. (1986). Calcium and delayed potassium currents in mouse pancreatic beta-cells under voltage-clamp conditions. J Physiol 374, 531–550.CrossRefGoogle Scholar
  27. Royle, S.J., and Lagnado, L. (2003). Endocytosis at the synaptic terminal. J Physiol 553, 345–355.CrossRefGoogle Scholar
  28. Srinivasan, K., and Ramarao, P. (2007). Animal models in type 2 diabetes research: an overview. Indian J Med Res 125, 451–472.Google Scholar
  29. Takei, K., Mundigl, O., Daniell, L., and De Camilli, P. (1996). The synaptic vesicle cycle: a single vesicle budding step involving clathrin and dynamin. J Cell Biol 133, 1237–1250.CrossRefGoogle Scholar
  30. Teng, H., Cole, J.C., Roberts, R.L., and Wilkinson, R.S. (1999). Endocytic active zones: hot spots for endocytosis in vertebrate neuromuscular terminals. J Neurosci 19, 4855–4866.Google Scholar
  31. Tsai, C.C., Lin, C.L., Wang, T.L., Chou, A.C., Chou, M.Y., Lee, C.H., Peng, I.W., Liao, J.H., Chen, Y.T., and Pan, C.Y. (2009). Dynasore inhibits rapid endocytosis in bovine chromaffin cells. Am J Physiol Cell Physiol 297, C397–406.CrossRefGoogle Scholar
  32. Wu, W., and Wu, L.G. (2007). Rapid bulk endocytosis and its kinetics of fission pore closure at a central synapse. Proc Natl Acad Sci U S A 104, 10234–10239.CrossRefGoogle Scholar
  33. Wu, X.S., McNeil, B.D., Xu, J., Fan, J., Xue, L., Melicoff, E., Adachi, R., Bai, L., and Wu, L.G. (2009). Ca(2+) and calmodulin initiate all forms of endocytosis during depolarization at a nerve terminal. Nat Neurosci 12, 1003–1010.CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.National Key Laboratory of Biomacromolecules, Institute of BiophysicsChinese Academy of SciencesBeijingChina
  2. 2.Lab of Cell Secretion and Metabolism, Institute of Molecular MedicinePeking University and National Center for Nanoscience and TechnologyBeijingChina
  3. 3.Department of General Surgery, Xuanwu HospitalCapital Medical UniversityBeijingChina
  4. 4.Graduate School of the Chinese Academy of SciencesBeijingChina

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