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Published 10 October 2005. doi:10.1083/jcb.200505179
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 1, 99-109
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Article

 Granuphilin molecularly docks insulin granules to the fusion machinery

Hiroshi Gomi1, Shin Mizutani1, Kazuo Kasai1, Shigeyoshi Itohara2, and Tetsuro Izumi1

1 Laboratory of Molecular Endocrinology and Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan
2 Laboratory for Behavioral Genetics, Brain Science Institute, Institute of Physical and Chemical Research, Saitama 351-0198, Japan

Correspondence to Tetsuro Izumi: tizumi{at}showa.gunma-u.ac.jp

The Rab27a effector granuphilin is specifically localized on insulin granules and is involved in their exocytosis. Here we show that the number of insulin granules morphologically docked to the plasma membrane is markedly reduced in granuphilin-deficient ß cells. Surprisingly, despite the docking defect, the exocytosis of insulin granules in response to a physiological glucose stimulus is significantly augmented, which results in increased glucose tolerance in granuphilin-null mice. The enhanced secretion in mutant ß cells is correlated with a decrease in the formation of the fusion-incompetent syntaxin-1a–Munc18-1 complex, with which granuphilin normally interacts. Furthermore, in contrast to wild-type granuphilin, its mutant that is defective in binding to syntaxin-1a fails to restore granule docking or the protein level of syntaxin-1a in granuphilin-null ß cells. Thus, granuphilin not only is essential for the docking of insulin granules but simultaneously imposes a fusion constraint on them through an interaction with the syntaxin-1a fusion machinery. These findings provide a novel paradigm for the docking machinery in regulated exocytosis.

Abbreviations used in this paper: ADV, adenovirus; HG, high-glucose; LG, low-glucose; MOI, multiplicity of infection.


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