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Molecular and Cellular Biology, August 2002, p. 5518-5526, Vol. 22, No. 15
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.15.5518-5526.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Granuphilin Modulates the Exocytosis of Secretory Granules through Interaction with Syntaxin 1a

Seiji Torii, Shengli Zhao, Zhaohong Yi, Toshiyuki Takeuchi, and Tetsuro Izumi*

Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan

Received 28 February 2002/ Returned for modification 16 April 2002/ Accepted 30 April 2002

The molecular mechanism for the regulated exocytosis of dense-core granules in endocrine cells remains relatively uncharacterized compared to that of synaptic vesicles in neurons. A novel set of Rab and its effector, Rab27a/granuphilin, which is localized on insulin granules in pancreatic beta cells, was recently identified. Here we demonstrate that granuphilin directly binds to syntaxin 1a on the plasma membrane, and this interaction is regulated by Rab27a. Granuphilin shows affinity to syntaxin 1a with a closed conformation but not to mutant syntaxin 1a, which adopts an open conformation constitutively. Overexpression of granuphilin significantly enhances basal insulin secretion but profoundly inhibits high K+-induced insulin secretion. The effect of granuphilin on insulin secretion was impaired by its mutation that disrupts the binding to either Rab27a or syntaxin 1a. Thus, granuphilin is the first regulator in the exocytotic pathway that functions by directly connecting two critical vesicle transport proteins, Rab and SNARE.

* Corresponding author. Mailing address: Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan. Phone: 81-27-220-8856. Fax: 81-27-220-8860. E-mail: tizumi{at}showa.gunma-u.ac.jp.

Molecular and Cellular Biology, August 2002, p. 5518-5526, Vol. 22, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.15.5518-5526.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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