Reduction of insulin-stimulated glucose uptake in L6 myotubes by the protein kinase inhibitor SB203580 is independent of p38MAPK activity

被引:54
作者
Antonescu, CN
Huang, C
Niu, W
Liu, Z
Eyers, PA
Heidenreich, KA
Bilan, PJ
Klip, A
机构
[1] Hosp Sick Children, Cell Biol Programme, Toronto, ON M5G 1X8, Canada
[2] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada
[3] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A8, Canada
[4] Univ Manchester, Sch Life Sci, Manchester M13 9PT, Lancs, England
[5] Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA
[6] Denver Vet Affairs Med Ctr, Denver, CO 80262 USA
关键词
D O I
10.1210/en.2005-0404
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Insulin increases glucose uptake through translocation of the glucose transporter GLUT4 to the plasma membrane. We previously showed that insulin activates p38MAPK, and inhibitors of p38MAPK alpha and p38MAPK beta (e. g. SB203580) reduce insulin-stimulated glucose uptake without affecting GLUT4 translocation. This observation suggested that insulin may increase GLUT4 activity via p38 alpha and/or p38 beta. 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 alpha (drug-resistant p38 alpha) but barely affected phosphorylation of the p38 substrate MAPK-activated protein kinase-2. Expression of dominant-negative p38 alpha or p38 beta reduced p38MAPK phosphorylation by 70% but had no effect on insulin-stimulated glucose uptake. Gene silencing via isoform-specific small interfering RNAs reduced expression of p38 alpha or p38 beta 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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页码:3773 / 3781
页数:9
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