Glucose transporter expression in L6 muscle cells: regulation through insulin- and stress-activated pathways.
We addressed the effect of long-term treatment with insulin, 2,4-dinitrophenol (DNP; an uncoupler of oxidative phosphorylation that increases energy demand) and 300 mM mannitol (hyperosmolarity) on glucose transporter (GLUT) expression in L6 muscle cells and the signaling pathways involved. We found the following. 1) The insulin-mediated increase in GLUT-1 is 70-kDa ribosomal protein S6 kinase (p70 S6 kinase) and p38 mitogen-activated protein kinase (MAPK) dependent but extracellular signal-regulated protein kinase (ERK) and MAPK/ERK kinase (MEK) independent. The hypertonicity-stimulated elevation in GLUT-1 is p70 S6 kinase, p38 MAPK, and MEK dependent yet ERK independent. DNP also increased GLUT-1 protein but did not depend on any of the above pathways, 2) Insulin increased GLUT-3 protein in a p70 S6 kinase-independent but MEK/ERK-dependent fashion. Inhibition of p38 MAPK potentiated the effect of insulin on GLUT-3. Hypertonicity increased GLUT-3 via p70 S6 kinase- and p38 MAPK-dependent pathways. In conclusion, we have dissected the molecular mechanisms used by insulin and hypertonicity that culminate in the induction of GLUT-1 and GLUT-3. The mechanism(s) used by DNP remains unknown.
Taha
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Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Tsakiridis
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McCall
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Klip
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D019297:2,4-Dinitrophenol / Q000494:pharmacology*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D006982:Hypertonic Solutions; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D008353:Mannitol / Q000494:pharmacology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D010766:Phosphorylation; D011090:Polyenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D020123:Sirolimus; D013312:Stress, Physiological; D014475:Uncoupling Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D006982:Hypertonic Solutions; D007093:Imidazoles; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009419:Nerve Tissue Proteins; D011090:Polyenes; D011725:Pyridines; C495678:Slc2a1 protein, mouse; C495689:Slc2a3 protein, mouse; D014475:Uncoupling Agents; D008353:Mannitol; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D019297:2,4-Dinitrophenol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D020123:Sirolimus