Key result
In a rat model of type 1 diabetes, cardiac ryanodine receptors acquired a gain-of-function phenotype with significantly increased open probability (0.85 vs 0.21) in response to cytoplasmic calcium.
RyR2 acquires a gain-of-function phenotype independent of its phosphorylation status during type 1 diabetes, providing a mechanism for enhanced spontaneous Ca2+ release in diabetic cardiomyopathy.
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RyR2 gain-of-function may promote Ca2+ leak in diabetic cardiomyopathy; leaves open translation to human disease or therapy.
AIMS: Ventricular myocytes isolated from hearts of streptozotocin (STZ)-diabetic rats exhibit increased spontaneous Ca(2+) release. Studies attribute this defect to an enhancement in activity of type 2 ryanodine receptor (RyR2). To date, underlying reasons for RyR2 dysregulation remain undefined. This study assesses whether the responsiveness of RyR2 following stimulation by intrinsic ligands is being altered during experimental type 1 diabetes (T1D). METHODS AND RESULTS: M-mode echocardiography established a cardiomyopathy in 8 weeks STZ-diabetic rats. Confocal microscopy confirmed an increase in the spontaneous Ca(2+) release in isolated ventricular myocytes. Western blots revealed no significant change in steady-state levels of the RyR2 protein. When purified to homogeneity and incorporated into planar lipid bilayers, RyR2 from STZ-diabetic rats (dRyR2) exhibited reduced current amplitude at ±35 mV. dRyR2 was also more responsive to intrinsic cytoplasmic activators Ca(2+), adenosine triphosphate, and cyclic adenosine diphosphate ribose and less responsive to the cytoplasmic deactivator Mg(2+). Threshold for the activation of RyR2 by trans (luminal) Ca(2+) was also reduced. These changes were independent of phosphorylation at Ser2808 and Ser2814. Two weeks of insulin treatment starting after 6 weeks of diabetes blunted the phenotype change, indicating that the gain of function is specific to the diabetes and not the result of STZ interacting directly with RyR2. CONCLUSION: These data show, for the first time, that RyR2 is acquiring a gain-of-function phenotype independent of its phosphorylation status during T1D and provides new insights for the enhanced spontaneous Ca(2+) release in myocytes from T1D rats.
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Tian et al. (2011) studied Type 1 Diabetes (Experimental Rat Model) (n=135). Streptozotocin-induced type 1 diabetes vs. Citrate buffer injection (Control) was evaluated on Mean open probability (Po) of RyR2 at 1.0 μM cis Ca2+ (p=<0.05). In a rat model of type 1 diabetes, cardiac ryanodine receptors acquired a gain-of-function phenotype with significantly increased open probability (0.85 vs 0.21) in response to cytoplasmic calcium.
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