Diabetes-related defects in sarcoplasmic Ca2+ release are prevented by inactivation of G alpha(11) and G alpha(q) in murine cardiomyocytes

作者：Hoyer Dieter Paul; Groenke Sabine; Frank Konrad F; Addicks Klaus; Wettschureck Nina; Offermanns Stefan; Erdmann Erland; Reuter Hannes^*

来源：Molecular and Cellular Biochemistry, 2010, 341(1-2): 235-244.

DOI：10.1007/s11010-010-0454-1

• Ryanodine receptor
• Type 1-diabetes
• Knockout mice
• Sorcin
• Annexin A7

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 G(q)-protein signaling via G alpha(11) and G alpha(q) 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, G alpha(11) knockout, and G alpha(11/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 Ca-45(2+) 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 G alpha(11)- and G alpha(11/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 G alpha(11)-knockout mice. G alpha(11/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 G(q)-proteins, G alpha(11) and G alpha(q), that could link increased neurohumoral stimulation in diabetes with defective RyR2 channel function by regulating protein expression of FKBP12.6, annexin A7, and sorcin.

• 出版日期2010-8