Document Detail

Two cAMP-dependent pathways differentially regulate exocytosis of large dense-core and small vesicles in mouse beta-cells.
MedLine Citation:
PMID:  17510178     Owner:  NLM     Status:  MEDLINE    
It has been reported that cAMP regulates Ca(2+)-dependent exocytosis via protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac) in neurons and secretory cells. It has, however, never been clarified how regulation of Ca(2+)-dependent exocytosis by cAMP differs depending on the involvement of PKA and Epac, and depending on two types of secretory vesicles, large dense-core vesicles (LVs) and small vesicles (SVs). In this study, we have directly visualized Ca(2+)-dependent exocytosis of both LVs and SVs with two-photon imaging in mouse pancreatic beta-cells. We found that marked exocytosis of SVs occurred with a time constant of 0.3 s, more than three times as fast as LV exocytosis, on stimulation by photolysis of a caged-Ca(2+) compound. The diameter of SVs was identified as approximately 80 nm with two-photon imaging, which was confirmed by electron-microscopic investigation with photoconversion of diaminobenzidine. Calcium-dependent exocytosis of SVs was potentiated by the cAMP-elevating agent forskolin, and the potentiating effect was unaffected by antagonists of PKA and was mimicked by the Epac-selective agonist 8-(4-chlorophenylthio)-2'-O-methyl cAMP, unlike that on LVs. Moreover, high-glucose stimulation induced massive exocytosis of SVs in addition to LVs, and photolysis of caged cAMP during glucose stimulation caused potentiation of exocytosis with little delay for SVs but with a latency of 5 s for LVs. Thus, Epac and PKA selectively regulate exocytosis of SVs and LVs, respectively, in beta-cells, and Epac can regulate exocytosis more rapidly than PKA.
Hiroyasu Hatakeyama; Noriko Takahashi; Takuya Kishimoto; Tomomi Nemoto; Haruo Kasai
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-05-17
Journal Detail:
Title:  The Journal of physiology     Volume:  582     ISSN:  0022-3751     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2007 Aug 
Date Detail:
Created Date:  2007-08-03     Completed Date:  2007-09-26     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1087-98     Citation Subset:  IM    
Division of Biophysics, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, 113-0033 Japan.
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MeSH Terms
Calcium / physiology
Cell Line
Cyclic AMP / physiology*
Cyclic AMP-Dependent Protein Kinases / metabolism
Cytoplasmic Vesicles / physiology
Exocytosis / physiology*
Insulin-Secreting Cells / cytology,  physiology*,  ultrastructure
Mice, Inbred ICR
Microscopy, Electron
Reg. No./Substance:
60-92-4/Cyclic AMP; 7440-70-2/Calcium; EC AMP-Dependent Protein Kinases

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