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 Ca.sup.2+ handling with functional defects of the sarcoplasmic reticulum (SR). The present study was therefore designed to determine the role of G.sub.q-protein signaling via Galpha.sub.11 and Gaq in diabetes for the induction of functional and structural changes in the Ca.sup.2+ release complex of the SR. An experimental type 1-diabetes was induced in wild type, Galpha.sub.11 knockout, and Galpha.sub.11/q- knockout mice by injection of streptozotocin. Cardiac morphology and function was assessed in vivo by echocardiography. SR Ca.sup.2+ leak was tested in vitro based on a sup.45Ca.sup.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 Ca.sup.2+ leak was increased. In addition, diabetic wild type animals showed reduced protein levels of FKBP12.6 and annexin A7. In Galpha.sub.11- and Galpha.sub.11/q-knockout animals, however, SR Ca.sup.2+ release and cardiac phenotype remained unchanged upon induction of diabetes. Densities of the proteins that we presently analyzed were also unaltered in Galpha.sub.11-knockout mice. Galpha.sub.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.sub.q-proteins, Galpha.sub.11 and Galpha.sub.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. Keywords Ryanodine receptor * Type 1-diabetes * Knockout mice * Sorcin * Annexin A7