Abnormal intracellular Ca²⁺ ([Ca²⁺]_i) handling by the sarcoplasmic reticulum (SR) is a critical factor in the development of heart failure (HF). Excitation-contraction coupling is predominantly controlled by Ca²⁺ release from the SR via the ryanodine receptor (RyR2). Release of Ca²⁺ via RyR2 is induced by Ca²⁺ influx through L-type Ca²⁺ channels and is modulated by multiple factors, including phosphorylation of RyR2 by protein kinase A, calmodulin kinase II and FKBP12.6. Hyperphosphorylation of RyR2 induces Ca²⁺ leak during diastole, which can cause fatal arrhythmias and lead to HF. This makes RyR2 an important therapeutic target.

We studied and confirmed the defective [Ca²⁺]_i signaling with both lower amplitude and slower kinetics of Ca²⁺ transients as well as the decreased SR Ca²⁺ load in diabetic rats. Furthermore we clearly established that these defects could be attributed to anomalous RyR2 behavior, as revealed by the spatio-temporal properties of Ca²⁺ sparks that especially exhibited slower kinetics. The reduced amount of RyR2 and FKBP12.6 levels and the PKA-dependent phosphorylation of RyR2 could be responsible for most of these observations. A lower SR Ca²⁺ load reinforced these defects in Ca²⁺ release channels.

We demonstrated that a beta-adrenergic receptor blocker, timolol treated diabetic rats exerted a protective action against anomalous Ca²⁺ homeostasis that was attributable to reduced RyR2 phosphorylation level, and recovery of protein levels of both RyR2 and FKBP12.6. Similar recoveries are also obtained by treating the diabetic rats with another beta-adrenergic receptor blocker, propranolol. We also showed that treatment of diabetic rats with these two beta-blockers restored the altered kinetic parameters of Ca²⁺ transients, depressed Ca²⁺ loading of SR and basal [Ca²⁺]_i. It is concluded that a detailed understanding of the basic structure and function of RyR2 will provide us their involvement in heart diseases, and the development of drugs to prevent RyR2 malfunction.

(Supported by TUBITAK-SBAG-107S427 and SBAG-107S304, COST BM0602).