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Diabetes-related defects in sarcoplasmic Ca2+ release are prevented by inactivation of Gα11 and Gαq in murine cardiomyocytes

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Abstract

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.

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Acknowledgments

Our special thanks go to Prof. Dr. A. Nögel (Institute of biochemistry of the University of Cologne) for providing the annexin A7 antibody. This study was supported by the German Heart Foundation/German Foundation of Heart Research (F/11/07 to H. Reuter). This work is part of the dissertation of D. Hoyer (University of Cologne, in preparation).

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Correspondence to Hannes Reuter.

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Hoyer, D.P., Grönke, S., Frank, K.F. et al. Diabetes-related defects in sarcoplasmic Ca2+ release are prevented by inactivation of Gα11 and Gαq in murine cardiomyocytes. Mol Cell Biochem 341, 235–244 (2010). https://doi.org/10.1007/s11010-010-0454-1

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  • DOI: https://doi.org/10.1007/s11010-010-0454-1

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