Endothelin-1 impairs glucose transporter trafficking via a membrane-based mechanism

Authors

  • Andrew B. Strawbridge,

    1. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana
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  • Jeffrey S. Elmendorf

    Corresponding author
    1. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana
    2. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana
    • 635 Barnhill Drive, MS308A, Indianapolis, Indiana 46202.
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Abstract

Endothelin-1 (ET-1) disrupts insulin-regulated glucose transporter GLUT4 trafficking. Since the negative consequence of chronic ET-1 exposure appears to be independent of signal disturbance along the insulin receptor substrate-1/phosphatidylinositol (PI) 3-kinase (PI3K)/Akt-2 pathway of insulin action, we tested if ET-1 altered GLUT4 regulation engaged by osmotic shock, a PI3K-independent stimulus that mimics insulin action. Regulation of GLUT4 by hyperosmotic stress was impaired by ET-1. Because of the mutual disruption of both insulin- and hyperosmolarity-stimulated GLUT4 translocation, we tested whether shared signaling and/or key phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated cytoskeletal events of GLUT4 trafficking were targets of ET-1. Both insulin and hyperosmotic stress signaling to Cbl were impaired by ET-1. Also, plasma membrane PIP2 and cortical actin levels were reduced in cells exposed to ET-1. Exogenous PIP2, but not PI 3,4,5-bisphosphate, restored actin structure, Cbl activation, and GLUT4 translocation. These data show that ET-1-induced PIP2/actin disruption impairs GLUT4 trafficking elicited by insulin and hyperosmolarity. In addition to showing for the first time the important role of PIP2-regulated cytoskeletal events in GLUT4 regulation by stimuli other than insulin, these studies reveal a novel function of PIP2/actin structure in signal transduction. J. Cell. Biochem. 97: 849–856, 2006. © 2005 Wiley-Liss, Inc.

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