An invited review following the Soujinkai Young Investigator Award : ryanodine receptor bound calmodulin as a novel therapeutic target of arrhythmias and heart failure

Life-threatening situations that can arise in patients with heart failure are widely recognized in clinical cardiology. This occasionally results from ventricular arrhythmias and hence the management of lethal arrhythmias is now one of the most important issues in the treatment of heart failure. In the failing cardiomyocytes, an abnormal regulation of intracellular calcium (Ca^{2+}) handling by a Ca^{2+} release channel of the sarcoplasmic reticulum (SR), so-called ryanodine receptor (RyR2), is known to play an important role in the mechanism underlying cardiac arrhythmias. On the other hand, in catecholaminergic polymorphic ventricular tachycardia (CPVT), mutation- linked defective channel gating of the RyR2 is also known as a major pathogenic mechanism underlying fatal arrhythmias. The knowledge gained from these studies upon the RyR2 and its modulatory proteins, such as calmodulin (CaM), may lead to the development of a new pharmacological or genetic strategy for the treatment of heart failure and cardiac arrhythmias. In this review, we focused on the role of CaM on the regulation of the channel gating of the RyR2 in the pathogenesis of heart failure and fatal arrhythmias, and discuss the possibility of developing a novel therapeutic strategy targeting the RyR2.

heart failure

lethal arrhythmia

cardiac ryanodine receptor

calmodulin