Bidirectional regulation of insulin receptor autophosphorylation and kinase activity by peroxynitrite.
Accumulating evidence suggests that enhanced peroxynitrite formation occurs during diabetes. This report describes the effect of peroxynitrite on insulin receptor (IR) function. Addition of peroxynitrite to purified IR resulted in concentration-dependent tyrosine nitration and thiol oxidation. Interestingly, the basal and insulin-stimulated IR autophosphorylation and tyrosine kinase activity were upregulated at low peroxynitrite concentrations, but downregulated at high peroxynitrite concentrations. Concomitantly, peroxynitrite dramatically reduced (125)I-insulin binding capacity and phosphotyrosine phosphatase activity of IR preparations. Moreover, SIN-1 administration decreased blood glucose levels in normal mice via upregulation of IR/IRS-1 tyrosine phosphorylation. In contrast, SIN-1 markedly increased blood glucose levels in diabetic mice concomitant with downregulation of IR/IRS-1 tyrosine phosphorylation. Taken together, these data provide new insights regarding how peroxynitrite influences IR function in vitro and in vivo, suggesting that peroxynitrite plays a dual role in regulation of IR autophosphorylation and tyrosine kinase activity, and SIN-1 has hyperglycemic effect in diabetic mice.
Zhou
Jun
J
Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, PR China.
He
Xingmu
X
Huang
Kaixun
K
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood / Q000201:enzymology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D009132:Muscles / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009574:Nitro Compounds / Q000378:metabolism; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
D001786:Blood Glucose; D009574:Nitro Compounds; D030421:Peroxynitrous Acid; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D017027:Protein Tyrosine Phosphatases