Alterations in ryanodine receptors and related proteins in heart failure

Abstract

Sarcoplasmic reticulum (SR) Ca(2+) release plays an essential role in mediating cardiac myocyte contraction. Depolarization of the plasma membrane results in influx of Ca(2+) through l-type Ca(2+) channels (LTCCs) that in turn triggers efflux of Ca(2+) from the SR through ryanodine receptor type-2 channels (RyR2). This process known as Ca(2+)-induced Ca(2+)release (CICR) occurs within the dyadic region, where the adjacent transverse (T)-tubules and SR membranes allow RyR2 clusters to release SR Ca(2+) following Ca(2+) influx through adjacent LTCCs. SR Ca(2+) released during systole binds to troponin-C and initiates actin-myosin cross-bridging, leading to muscle contraction. During diastole, the cytosolic Ca(2+) concentration is restored by the resequestration of Ca(2+) into the SR by SR/ER Ca(2+)-ATPase (SERCA2a) and by the extrusion of Ca(2+) via the Na(+)/Ca(2+)-exchanger (NCX1). This whole process, entitled excitation-contraction (EC) coupling, is highly coordinated and determines the force of contraction, providing a link between the electrical and mechanical activities of cardiac muscle. In response to heart failure (HF), the heart undergoes maladaptive changes that result in depressed intracellular Ca(2+) cycling and decreased SR Ca(2+) concentrations. As a result, the amplitude of CICR is reduced resulting in less force production during EC coupling. In this review, we discuss the specific proteins that alter the regulation of Ca(2+) during HF. In particular, we will focus on defects in RyR2-mediated SR Ca(2+) release. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.

Keywords: Calcium; Contractility; Heart failure; Ryanodine receptor; Sarcoplasmic reticulum.

Figure 1

Schematic representation of changes in Type 2 Ryanodine receptors (RyR2) and related proteins in heart failure (HF). Left, represents Ca²⁺ handling in a cell from normal heart, and right, represents Ca²⁺ handling in a cell from a failing heart. 1) shows increased RyR2 activity represented by a wide open RyR2 due to post-translational modification by increased protein kinase A (PKA) and Ca²⁺/CaM-dependent protein kinase II (CaMKII) activity, reduced protein phosphatases (PP) 1 and PP 2A activity, reduced junctophilin 2 (JPH2) leading to abnormalities in T-tubule structure and increased oxidation by reactive oxygen species (ROS), 2) represents complex changes in L-type Ca²⁺ channel (LTCC) as discussed in the text, 3) represents reduced SR/ER Ca²⁺-ATPase (SERCA2a) activity and corresponding increased phospholamban (PLN) and Sarcolipin (SLN) activity, and 4) represents increased Na⁺/Ca²⁺ exchanger (NCX) activity, in heart failure. ↑ represents increase and ↓ represents decrease.