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J. Biol. Chem., Vol. 283, Issue 16, 10716-10726, April 18, 2008

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Filamentous Actin Regulates Insulin Exocytosis through Direct Interaction with Syntaxin 4^*

Jenna L. Jewell¹, Wei Luo¹, Eunjin Oh, Zhanxiang Wang, and Debbie C. Thurmond²

From the Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, Indiana 46202 and GenScript Corporation, Piscataway, New Jersey 08854

Glucose-induced insulin exocytosis is coupled to associations between F-actin and SNARE proteins, although the nature and function of these interactions remains unknown. Toward this end we show here that both Syntaxin 1A and Syntaxin 4 associated with F-actin in MIN6 cells and that each interaction was rapidly and transiently diminished by stimulation of cells with D-glucose. Of the two isoforms, only Syntaxin 4 was capable of interacting directly with F-actin in an in vitro sedimentation assay, conferred by the N-terminal 39-112 residues of Syntaxin 4. The 39-112 fragment was capable of selective competitive inhibitory action, disrupting endogenous F-actin-Syntaxin 4 binding in MIN6 cells. Disruption of F-actin-Syntaxin 4 binding correlated with enhanced glucose-stimulated insulin secretion, mediated by increased granule accumulation at the plasma membrane and increased Syntaxin 4 accessibility under basal conditions. However, no increase in basal level Syntaxin 4-VAMP2 association occurred with either latrunculin treatment or expression of the 39-112 fragment. Taken together, these data disclose a new underlying mechanism by which F-actin negatively regulates exocytosis via binding and blocking Syntaxin 4 accessibility, but they also reveal the existence of additional signals and/or steps required to trigger the subsequent docking and fusion steps of exocytosis.

Received for publication, December 4, 2007 , and in revised form, February 13, 2008.

^* This work was supported by Grants DK-067912 and DK-76614 from the National Institutes of Health and 1-03-CD-10 from the American Diabetes Association (to D. C. T.) and Postdoctoral Fellowship 0720042Z from the American Heart Association (to E. O.). 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.

¹ These authors contributed equally.

² To whom correspondence should be addressed: 635 Barnhill Dr., MS4053, Dept. of Biochemistry and Molecular Biology, Indianapolis, IN 46202. Tel.: 317-274-1551; Fax: 317-274-4686; E-mail: dthurmon{at}iupui.edu.

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