Alterations in ryanodine receptors and related proteins in heart failure

AbstractSarcoplasmic reticulum (SR) Ca2+ release plays an essential role in mediating cardiac myocyte contraction. Depolarization of the plasma membrane results in influx of Ca2+ through l-type Ca2+ channels (LTCCs) that in turn triggers efflux of Ca2+ from the SR through ryanodine receptor type-2 channels (RyR2). This process known as Ca2+-induced Ca2+release (CICR) occurs within the dyadic region, where the adjacent transverse (T)-tubules and SR membranes allow RyR2 clusters to release SR Ca2+ following Ca2+ influx through adjacent LTCCs. SR Ca2+ released during systole binds to troponin-C and initiates actin–myosin cross-bridging, leading to muscle contraction. During diastole, the cytosolic Ca2+ concentration is restored by the resequestration of Ca2+ into the SR by SR/ER Ca2+-ATPase (SERCA2a) and by the extrusion of Ca2+ via the Na+/Ca2+-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 Ca2+ cycling and decreased SR Ca2+ 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 Ca2+ during HF. In particular, we will focus on defects in RyR2-mediated SR Ca2+ release. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions