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The cardiac ryanodine receptor (RyR2) plays an important role in regulating contraction of the heart. During exercise or stress, the heart contracts more frequently and with more force in order to supply more oxygenated blood to the body. Therefore, the activity of the ryanodine receptor is increased during exercise. By clicking on the respective model figures, you can see how the function of the ryanodine receptor is regulated in the normal heart and during exercise.

Dysfunction of the cardiac ryanodine receptor has been linked to several diseases, including heart failure and exercise-induced sudden cardiac death. Patients with heart failure typically have increased plasma levels of catecholamines (in order to compensate for the decreased function of the heart). Increased catecholamines will lead to long-term activation of the beta-adrenergic receptors, which will cause hyperphosphorylation of RyR2 by protein kinase A. Hyperphosphorylated RyR2 may become 'leaky' indicating a compromised closed state of the Ca2+ release channel, resulting in depletion of Ca2+ from intracellular Ca2+ stores called the sarcoplasmic reticulum (SR). The net result of chronic RyR2 Ca2+ leak is a reduction in the amount of Ca2+ available during each cycle of cardiac contraction (systole) further contributing to depressed cardiac function (see HEART FAILURE) as well as abnormal Ca2+ leak during relaxation (diastole) potentially contributing to Ca2+ induced arrhythmias and sudden death.

Patients with inherited mutations in the cardiac ryanodine receptor gene (hRyR2) develop ventricular arrhythmias and sudden cardiac death in the absence of structural heart disease referred to as Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT-1). During exercise, when the ryanodine receptor becomes physiologically phosphorylated by protein kinase A (PKA), the mutant RyR2 channels may become 'leaky' because they lose more of the channel stabilizing protein calstabin2 due to a reduced binding affinity (as compared to normal wild-type RyR2 from healthy individuals). Exercise-induced Ca2+ leak during diastole may initiate ventricular arrhythmias and sudden cardiac death which occurs in up to 50% of RyR2 mutation carriers at age 35.

In any form of heart disease which results in Ca2+ leak from the cardiac ryanodine receptor, both in heart failure and in CPVT-1 resulting from hRyR2 mutations, it is highly desirable to understand the molecular mechanisms of defective channel function. Characterization of calstabin2 as a channel stabilizing subunit has led to the realization that increased binding of calstabin2 to leaky RyR2 can protect from abnormal Ca2+ leak in heart disease. On the basis of this concept a novel drug class, Ca2+ release channel stabilizers, has been identified which have shown efficacy in animal models of heart failure or exercise-induced arrhythmias. Thus, Ca2+ release channel stabilizing drugs may provide a disease mechanism-targeted therapeutic rationale against lethal arrhythmias and heart failure progression which is urgently needed due to the high number of patients at risk for lethal arrhythmias or heart failure.