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J. Biol. Chem., Vol. 282, Issue 46, 33530-33536, November 16, 2007

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Dynamin Is Functionally Coupled to Insulin Granule Exocytosis^*

Le Min, Yuk M. Leung^¶1, Alejandra Tomas^||, Robert T. Watson, Herbert Y. Gaisano, Philippe A. Halban^||, Jeffrey E. Pessin, and June Chunqiu Hou²

From the Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794, the Departments of Medicine and Physiology, University of Toronto, Toronto M5S 1A8, Canada, the ^¶Department of Physiology, China Medical University, Taichung 404, Taiwan, and the ^||Department of Genetic Medicine and Development, Centre Médical Universitaire, 1 rue Michel-Servet, 1211 Geneva, Switzerland

The insulin granule integral membrane protein marker phogrin-green fluorescent protein was co-localized with insulin in Min6B1 -cell secretory granules but did not undergo plasma membrane translocation following glucose stimulation. Surprisingly, although expression of a dominant-interfering dynamin mutant (Dyn/K44A) inhibited transferrin receptor endocytosis, it had no effect on phogringreen fluorescent protein localization in the basal or secretagogue-stimulated state. By contrast, co-expression of Dyn/K44A with human growth hormone as an insulin secretory marker resulted in a marked inhibition of human growth hormone release by glucose, KCl, and a combination of multiple secretagogues. Moreover, serial pulse depolarization stimulated an increase in cell surface capacitance that was also blocked in cells expressing Dyn/K44A. Similarly, small interference RNA-mediated knockdown of dynamin resulted in marked inhibition of glucose-stimulated insulin secretion. Together, these data suggest the presence of a selective kiss and run mechanism of insulin release. Moreover, these data indicate a coupling between endocytosis and exocytosis in the regulation of -cell insulin secretion.

Received for publication, April 24, 2007 , and in revised form, August 16, 2007.

^* This work was supported in part by National Institutes of Health Grants DK33823 and DK55811, by the Swiss National Science Fund (Grants 3200B0-101902 and 310000-113967/1), and by the Canadian Institute of Health (Grant MOP-64465). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data and Figs. S1–S3.

¹ Recipient of a post-doctoral fellowship from the Canadian Diabetes Association.

² To whom correspondence should be addressed: Dept. of Pharmacological Sciences, Stony Brook University, BST8-140, Stony Brook, NY 11794-8651. Tel.: 631-444-3059; Fax: 631-444-3022; E-mail: Hou{at}pharm.stonybrook.edu.

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