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Submitted on October 1, 2004
Accepted on January 10, 2005
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK; and EDMNS/DB, NIDDK, National Institutes of Health, Bethesda, MD 20892-0842, USA
* To whom correspondence should be addressed. E-mail: g.d.holman{at}bath.ac.uk.
The translocation of GLUT4 to the cell surface is a complex multi-step process that involves movement of GLUT4 vesicles from a reservoir compartment, and docking and fusion of the vesicles with the plasma membrane. It has recently been proposed that a p38 MAP kinase-dependent step may further lead to intrinsic activation of the transporters exposed at the cell surface. In contrast to data obtained in muscle and adipocyte cell lines, we found that no insulin activation of p38 MAP kinase occurred in rat adipose cells. However, the p38 MAP kinase inhibitor SB203580 consistently inhibited transport activity following a pre-incubation with the adipose cells. These apparently contradictory findings led us to hypothesize that the inhibitor may have a direct effect on the transport catalytic activity of GLUT4 that was independent of inhibition of the kinase. Kinetic analysis of 3-O-methyl-D-glucose transport activity revealed that SB203580 was a non-competitive inhibitor of zero-trans (substrate outside but not inside) transport but was a competitive inhibitor of equilibrium-exchange (substrate inside and outside) transport. This pattern of inhibition of GLUT4 was also observed with cytochalasin B. The pattern of inhibition is consistent with interaction at the endofacial surface but not the exofacial surface of the transporter. Occupation of the endofacial substrate site reduces Vmax under zero-trans conditions as return of the substrate site to the outside is blocked and no substrate is present inside to displace the inhibitor. Under equilibrium-exchange conditions, internal substrate competitively displaces the inhibitor and the transport Km is increased.
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