title: 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.
authors.affiliation: Dept of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Dept of Medicine (Cardiology), Baylor College of Medicine, Houston, TX, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Ather
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Respress
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D019837:Ryanodine Receptor Calcium Release Channel
keywords: Calcium; Contractility; Heart failure; Ryanodine receptor; Sarcoplasmic reticulum