Endothelin-1 impairs glucose transporter trafficking via a membrane-based mechanism.
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.
Strawbridge
Andrew B
AB
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana, USA.
Elmendorf
Jeffrey S
JS
D041721:3T3-L1 Cells; D000818:Animals; D002462:Cell Membrane / Q000502:physiology*; D019332:Endothelin-1 / Q000494:pharmacology*; D051275:Glucose Transporter Type 4 / Q000235:genetics* / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D009004:Monosaccharide Transport Proteins; D050722:Oncogene Protein v-cbl / Q000378:metabolism; D009997:Osmotic Pressure; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D019332:Endothelin-1; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D050722:Oncogene Protein v-cbl; C112403:PIP3-APB; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D014443:Tyrosine