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Submitted on April 7, 2005
Accepted on May 31, 2005
Programme in Cell Biology, The Hospital For Sick Children, Toronto, Ontario, Canada, M5G 1X8; Department of Biochemistry, University of Toronto, Ontario, Canada, M5S 1A8; Institute of Medical Sciences, University of Toronto, Ontario, Canada, M5S 1A8; School of Life Sciences, The Michael Smith Building, University of Manchester, Manchester, M13 9PT, UK; Department of Pharmacology, University of Colorado Health Sciences Center, and Denver Veterans Affairs Medical Center, Denver, Colorado 80262, USA
* To whom correspondence should be addressed. E-mail: amira{at}sickkids.ca.
Insulin increases glucose uptake through translocation of the glucose transporter GLUT4 to the plasma membrane. We previously showed that insulin activates p38 mitogen-activated protein kinase (p38MAPK), and inhibitors of p38MAPK
and p38MAPK
(e.g. SB203580) reduce insulin-stimulated glucose uptake without affecting GLUT4 translocation. This observation suggested that insulin may increase GLUT4 activity via p38 and/or p38. Here we further explore the possible participation of p38MAPK through a combination of molecular strategies. SB203580 reduced insulin stimulation of glucose uptake in L6 myotubes overexpressing an SB203580-resistant p38 (DR-p38), but barely affected phosphorylation of the p38 substrate MAPKAPK-2 (MK-2). Expression of dominant-negative p38 or p38 reduced p38MAPK phosphorylation by 70% but had no effect on insulin-stimulated glucose uptake. Gene silencing via isoform-specific siRNAs reduced expression of p38 or p38 by 60-70% without diminishing insulin-stimulated glucose uptake. SB203580 reduced photoaffinity labeling of GLUT4 by Bio-LC-ATB-BMPA only in the insulin-stimulated state. Unless low levels of p38MAPK suffice to regulate glucose uptake, these results suggest that the inhibition of insulin-stimulated glucose transport by SB203580 is likely not mediated by p38MAPK. Instead, changes experienced by insulin-stimulated GLUT4 make it susceptible to inhibition by SB203580.
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