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Glucose-Stimulated Insulin Secretion Is Coupled to the Interaction of Actin with the t-SNARE (Target Membrane Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor Protein) Complex

Department of Biochemistry and Molecular Biology (D.C.T.), Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Physiology and Biophysics (M.F., J.E.P.), The University of Iowa, Iowa City, Iowa 52242; and Laboratoires Jeantet (C.G.-G., P.A.H.), University Medical Center, 1211 Geneva 4, Switzerland

Address all correspondence and requests for reprints to: Debbie C. Thurmond, Ph.D., Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, Indiana 46202. E-mail: dthurmon{at}iupui.edu.

The actin monomer sequestering agent latrunculin B depolymerized ß-cell cortical actin, which resulted in increased glucose-stimulated insulin secretion in both cultured MIN6 ß-cells and isolated rat islet cells. In perifused islets, latrunculin B treatment increased both first- and second-phase glucose-stimulated insulin secretion without any significant effect on total insulin content. This increase in secretion was independent of calcium regulation because latrunculin B also potentiated calcium-stimulated insulin secretion in permeabilized MIN6 cells. Confocal immunofluorescent microscopy revealed a redistribution of insulin granules to the cell periphery in response to glucose or latrunculin B, which correlated with a reduction in phalloidin staining of cortical actin. Moreover, the t-SNARE [target membrane soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor] proteins Syntaxin 1 and SNAP-25 coimmunoprecipitated polymerized actin from unstimulated MIN6 cells. Glucose stimulation transiently decreased the amount of actin coimmunoprecipitated with Syntaxin 1 and SNAP-25, and latrunculin B treatment fully ablated the coimmunoprecipitation. In contrast, the actin stabilizing agent jasplakinolide increased the amount of actin coimmunoprecipitated with the t-SNARE complex and prevented its dissociation upon glucose stimulation. These data suggest a mechanism whereby glucose modulates ß-cell cortical actin organization and disrupts the interaction of polymerized actin with the plasma membrane t-SNARE complex at a distal regulatory step in the exocytosis of insulin granules.

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