RyR2 and Calcium Release in Heart Failure

Abstract

Heart Failure (HF) is defined as the inability of the heart to efficiently pump out enough blood to maintain the body's needs, first at exercise and then also at rest. Alterations in Ca²⁺ handling contributes to the diminished contraction and relaxation of the failing heart. While most Ca²⁺ handling protein expression and/or function has been shown to be altered in many models of experimental HF, in this review, we focus in the sarcoplasmic reticulum (SR) Ca²⁺ release channel, the type 2 ryanodine receptor (RyR2). Various modifications of this channel inducing alterations in its function have been reported. The first was the fact that RyR2 is less responsive to activation by Ca²⁺ entry through the L-Type calcium channel, which is the functional result of an ultrastructural remodeling of the ventricular cardiomyocyte, with fewer and disorganized transverse (T) tubules. HF is associated with an elevated sympathetic tone and in an oxidant environment. In this line, enhanced RyR2 phosphorylation and oxidation have been shown in human and experimental HF. After several controversies, it is now generally accepted that phosphorylation of RyR2 at the Calmodulin Kinase II site (S2814) is involved in both the depressed contractile function and the enhanced arrhythmic susceptibility of the failing heart. Diminished expression of the FK506 binding protein, FKBP12.6, may also contribute. While these alterations have been mostly studied in the left ventricle of HF with reduced ejection fraction, recent studies are looking at HF with preserved ejection fraction. Moreover, alterations in the RyR2 in HF may also contribute to supraventricular defects associated with HF such as sinus node dysfunction and atrial fibrillation.

Keywords: atrial fibrillation; calcium; excitation contraction coupling; heart failure; ryanodine receptor; sinus node.

Figure 1

Main elements of Ca²⁺ handling in excitation-contraction coupling in a ventricular cardiomyocyte. (A) Scheme of a portion of a ventricular cardiomyocyte showing two T-tubules, with L type Ca²⁺ channels (LTCC) and the Na⁺/Ca²⁺ exchanger (NCX), and the junctional sarcoplasmic reticulum with Ryanodine Receptors (RyR2). Plasmalema and SarcoEndoplasmic Ca²⁺ ATPases (PMCA and SERCA) are also shown, with phospholamban (PLN) which slows SERCA activity, as well as the mitochondrial Ca²⁺ uniporter (MCU). The black arrows indicate Ca²⁺ movements during the action potential (drawing on top left), producing the [Ca²⁺]_i transient (confocal line scan image on top). (B) The same elements during rest. The LTCC are inactive, and the RyR2 closed, with small leak. (C) and (D) The same as in (A) and (B) but in heart failure: the density of T-tubules is decreased as well as SERCA expression; the RyR2 are more active.