Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8324616 | The International Journal of Biochemistry & Cell Biology | 2012 | 11 Pages |
Abstract
Our previous studies demonstrated that acetylated tubulin forms a complex with Na+,K+-ATPase and thereby inhibits its enzyme activity in cultured COS and CAD cells. The enzyme activity was restored by treatment of cells with l-glutamate, which caused dissociation of the acetylated tubulin/Na+,K+-ATPase complex. Addition of glucose, but not elimination of glutamate, led to re-formation of the complex and inhibition of the Na+,K+-ATPase activity. The purpose of the present study was to elucidate the mechanism underlying this effect of glucose. We found that exposure of cells to high glucose concentrations induced: (a) microtubule formation; (b) activation of aldose reductase by the microtubules; (c) association of tubulin with membrane; (d) formation of the acetylated tubulin/Na+,K+-ATPase complex and consequent inhibition of enzyme activity. Exposure of cells to sorbitol caused similar effects. Studies on erythrocytes from diabetic patients and on tissues containing insulin-insensitive glucose transporters gave similar results. Na+,K+-ATPase activity was >50% lower and membrane-associated tubulin content was >200% higher in erythrocyte membranes from diabetic patients as compared with normal subjects. Immunoprecipitation analysis showed that acetylated tubulin was a constituent of a complex with Na+,K+-ATPase in erythrocyte membranes from diabetic patients. Based on these findings, we propose a mechanism whereby glucose triggers a synergistic effect of tubulin and sorbitol, leading to activation of aldose reductase, microtubule formation, and consequent Na+,K+-ATPase inhibition.
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Authors
Juan F. Rivelli, Marina R. Amaiden, Noelia E. Monesterolo, Gabriela Previtali, Verónica S. Santander, Adriana Fernandez, Carlos A. Arce, Cesar H. Casale,