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Diabetes-related defects in sarcoplasmic Ca 2+ release are prevented by inactivation of Gα 11 and Gα q in murine cardiomyocytes

Diabetes-related defects in sarcoplasmic Ca 2+ release are prevented by inactivation of Gα 11 and Gα q in murine cardiomyocytes,10.1007/s11010-010-045

Diabetes-related defects in sarcoplasmic Ca 2+ release are prevented by inactivation of Gα 11 and Gα q in murine cardiomyocytes  
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Neurohumoral stimulation of Gq-coupled receptors has been proposed as a central mechanism in the pathogenesis of diabetic heart disease. The resulting contractile dysfunction is closely related to abnormal intracellular Ca2+ handling with functional defects of the sarcoplasmic reticulum (SR). The present study was therefore designed to determine the role of Gq-protein signaling via Gα11 and Gαq in diabetes for the induction of functional and structural changes in the Ca2+ release complex of the SR. An experimental type 1-diabetes was induced in wild type, Gα11 knockout, and Gα11/q-knockout mice by injection of streptozotocin. Cardiac morphology and function was assessed in vivo by echocardiography. SR Ca2+ leak was tested in vitro based on a 45Ca2+ assay and protein densities as well as gene expression of ryanodine receptor (RyR2), FKBP12.6, sorcin, and annexin A7 were analyzed by immunoblot and RT-PCR. In wild type animals 8 weeks of diabetes resulted in cardiac hypertrophy and SR Ca2+ leak was increased. In addition, diabetic wild type animals showed reduced protein levels of FKBP12.6 and annexin A7. In Gα11- and Gα11/q-knockout animals, however, SR Ca2+ release and cardiac phenotype remained unchanged upon induction of diabetes. Densities of the proteins that we presently analyzed were also unaltered in Gα11-knockout mice. Gα11/q-knockout animals even showed increased expression of sorcin and annexin A7. Thus, based on the present study we suggest a signaling pathway via the Gq-proteins, Gα11 and Gαq, that could link increased neurohumoral stimulation in diabetes with defective RyR2 channel function by regulating protein expression of FKBP12.6, annexin A7, and sorcin.
Journal: Molecular and Cellular Biochemistry - MOL CELL BIOCHEM , vol. 341, no. 1, pp. 235-244, 2010
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