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J. Biol. Chem., Vol. 280, Issue 27, 25565-25570, July 8, 2005

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Mammalian Exocyst Complex Is Required for the Docking Step of Insulin Vesicle Exocytosis^*

Takashi Tsuboi, Magalie A. Ravier, Hao Xie¶, Marie-Ann Ewart||, Gwyn W. Gould||**, Stephen A. Baldwin¶, and Guy A. Rutter

From the Henry Wellcome Laboratories for Integrated Cell Signalling and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, United Kingdom, ^||Henry Wellcome Laboratory of Cell Biology, Division of Biochemistry and Molecular Biology, Davidson Building, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom, and ^¶School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT, United Kingdom

Glucose stimulates insulin secretion from pancreatic cells by inducing the recruitment and fusion of insulin vesicles to the plasma membrane. However, little is currently known about the mechanism of the initial docking or tethering of insulin vesicles prior to fusion. Here, we examined the role of the SEC6-SEC8 (exocyst) complex, implicated in trafficking of secretory vesicles to fusion sites in the plasma membrane in yeast and in regulating glucose-stimulated insulin secretion from pancreatic MIN6 cells. We show first that SEC6 is concentrated on insulin-positive vesicles, whereas SEC5 and SEC8 are largely confined to the cytoplasm and the plasma membrane, respectively. Overexpression of truncated, dominant-negative SEC8 or SEC10 mutants decreased the number of vesicles at the plasma membrane, whereas expression of truncated SEC6 or SEC8 inhibited overall insulin secretion. When single exocytotic events were imaged by total internal reflection fluorescence microscopy, the fluorescence of the insulin surrogate, neuropeptide Y-monomeric red fluorescent protein brightened, diffused, and then vanished with kinetics that were unaffected by overexpression of truncated SEC8 or SEC10. Together, these data suggest that the exocyst complex serves to selectively regulate the docking of insulin-containing vesicles at sites of release close to the plasma membrane.

Received for publication, February 14, 2005 , and in revised form, April 28, 2005.

^* This work was supported in part by grants (to G. A. R.) from the Wellcome Trust (Project 062321; Programme 067081/Z/02/Z), the Biotechnology and Biological Sciences Research Council, the Human Frontiers Science Program, the Juvenile Diabetes Research Foundation, and Diabetes UK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Juvenile Diabetes Research Foundation International postdoctoral fellowship.

^** Supported by Biotechnology and Biological Sciences Research Council Grant 17/C12621 and recipient of a Wellcome Trust for Research leave fellowship.

Supported by Biotechnology and Biological Sciences Research Council Grant 24/b17173.

Recipient of a Wellcome Trust for Research leave fellowship. To whom correspondence should be addressed: Dept. of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom. Tel.: 44-117-954-6401; Fax: 44-117-928-8274; E-mail: g.a.rutter{at}bristol.ac.uk.

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