The ryanodine receptor in cardiac physiology and disease

Abstract

According to the American Heart Association it is estimated that the United States will spend close to $39 billion in 2010 to treat over five million Americans suffering from heart failure. Patients with heart failure suffer from dyspnea and decreased exercised tolerance and are at increased risk for fatal ventricular arrhythmias. Food and Drug Administration -approved pharmacologic therapies for heart failure include diuretics, inhibitors of the renin-angiotensin system, and β-adrenergic receptor antagonists. Over the past 20 years advances in the field of ryanodine receptor (RyR2)/calcium release channel research have greatly advanced our understanding of cardiac physiology and the pathogenesis of heart failure and arrhythmias. Here we review the key observations, controversies, and discoveries that have led to the development of novel compounds targeting the RyR2/calcium release channel for treating heart failure and for preventing lethal arrhythmias.

FIGURE 1

Cardiac action potential: Depolarization is initiated by opening of voltage-gated Na⁺ channels followed by the opening of voltage-gated Ca²⁺ and K⁺ channels. Influx of Ca²⁺ into the cytosol during phase 2 of the cardiac action potential triggers Ca²⁺ release from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RyR2). Baseline [Na⁺] and [K⁺] are restored by the Na⁺/K⁺ ATPase (NKA). RyR2 is a homotetrameric macromolecular complex.

FIGURE 2

Arrhythmias induced by cytosolic Ca²⁺ overload: (A) Elevated cytosolic [Ca²⁺] causes transient inward current through the Na⁺/Ca²⁺ exchanger (NCX) which can generate delayed after depolarizations (DADs). (B) Cardiomyocytes eliciting DADs can become ectopic foci of automaticity which can evolve into reentry circuits to cause (C) premature ventricular contractions (PVCs) on the electrocardiogram (ECG). (D) If uncorrected this may deteriorate into ventricular fibrillation (VF) and sudden cardiac death.

FIGURE 3

Mechanisms of RyR2 Ca²⁺ leak in HF: (A) PKA hyperphosphorylation of RyR2 at Ser2808 and depletion of calstabin2 from the channel causes SR Ca²⁺ leak. (D) The therapeutic efficacy of JTV-519 is based on the ability of the drug to stabilize the interaction between calstabin2 and RyR2. (B) Store overload-induced Ca²⁺ release (SOICR), RyR2 has increased sensitivity to luminal [Ca²⁺] which causes Ca²⁺ to leak out of the channel. (E) According to this model JTV-519 stabilizes RyR2 independent of calstabin2. (C) Unzipping of the amino and central domains of RyR2 causes the channel to become leaky. (F) JTV-519 stabilizes the zipped state of the channel.