Alterations in ryanodine receptors and related proteins in heart failure

Sarcoplasmic 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.