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Endothelin‐1 impairs glucose transporter trafficking via a membrane‐based mechanism
Author(s) -
Strawbridge Andrew B.,
Elmendorf Jeffrey S.
Publication year - 2005
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20687
Subject(s) - glut4 , glucose transporter , microbiology and biotechnology , actin cytoskeleton , phosphatidylinositol , insulin receptor , signal transduction , biology , insulin , pi3k/akt/mtor pathway , cytoskeleton , medicine , endocrinology , insulin resistance , biochemistry , cell
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 (PIP 2 )‐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 PIP 2 and cortical actin levels were reduced in cells exposed to ET‐1. Exogenous PIP 2 , but not PI 3,4,5‐bisphosphate, restored actin structure, Cbl activation, and GLUT4 translocation. These data show that ET‐1‐induced PIP 2 /actin disruption impairs GLUT4 trafficking elicited by insulin and hyperosmolarity. In addition to showing for the first time the important role of PIP 2 ‐regulated cytoskeletal events in GLUT4 regulation by stimuli other than insulin, these studies reveal a novel function of PIP 2 /actin structure in signal transduction. J. Cell. Biochem. 97: 849–856, 2006. © 2005 Wiley‐Liss, Inc.