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.