Phenylarsine oxide inhibits insulin-stimulated protein phosphatase 1 activity and GLUT-4 translocation.
Phenylarsine oxide (PAO) has previously been shown to inhibit insulin-stimulated glucose transport without affecting insulin binding and tyrosine kinase activity of insulin receptor (S. C. Frost and M. D. Lane. J. Biol. Chem. 260: 2646-2652, 1985). This study examines the effect of PAO on insulin's ability to activate adipocyte protein phosphatase 1 (PP-1) and dephosphorylate GLUT-4, the insulin-sensitive glucose transporter. In particulate fractions, insulin stimulated PP-1 activity (40% increase over basal with phosphorylase a) in a time- and dose-dependent manner (half-maximal effect of 0.89 nM in 1 min). Insulin did not alter cytosolic PP-1 activity. With GLUT-4 as a substrate, insulin caused more than twofold stimulation of particulate PP-1 activity. Addition of PAO (5 microM) before or after insulin treatment abolished insulin's effect on PP-1 activation. The presence of 2,3-dimercaptopropanol (200 microM) prevented the effect of PAO on PP-1 activation and glucose uptake. In addition, PAO significantly increased GLUT-4 phosphorylation, blocked insulin-stimulated dephosphorylation, and partially diminished insulin-stimulated translocation of GLUT-4. We conclude that PAO may interfere with the components of insulin signal transduction pathways that lead to the activation of PP-1 and this may be responsible for the observed inhibition in insulin action.
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Diabetes Research Laboratory, Winthrop University Hospital, Mineola 11501.
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D051381:Rats; D017207:Rats, Sprague-Dawley
D001152:Arsenicals; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; C029341:oxophenylarsine; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1