Regulation of sarcoplasmic reticulum Ca2+-ATPase and phospholamban in the failing and nonfailing heart

The mammalian organism responds to chronic pressure and volume overload of the heart with a plethora of adaptive changes that consist of resetting of the neurohumoral homeostasis on a more general level and of structural remodeling and functional alterations on the cellular level. These latter changes include electrophysiological properties as exemplified by prolongation in action potential duration and rhythm disturbances considered responsible for sudden cardiac death as well as depression in contractile function of individual myocytes. Since calcium ions (Ca2+) play a pivotal role in cardiac excitation–contraction coupling, contractile dysfunction has been interpreted as a defect in Ca2+-handling proteins of the sarcoplasmic reticulum (SR) at the subcellular level. This survey begins with a brief outline of cardiac excitation–contraction coupling and the functional role of the SR Ca2+-ATPase and its regulatory protein phospholamban. It continues with a summary of a frequently cited paper on the modulatory changes in these two Ca2+ homeostasis regulating proteins in human heart failure [1] and it will then discuss the confirmatory and controversial issues published since that seminal work appeared. The review will conclude with recently defined deficiencies at other subcellular sites. In its course, the reader is frequently referred to the excellent reviews of our current knowledge on the topic, which were compiled in the 1998 focused issue of this journal [2–7]. Contraction of heart muscle is initiated by electrical excitation of the plasmalemma followed by the typical long lasting cardiac action potential. Calcium entering the myocytes during the plateau phase of the action potential mainly via voltage sensitive L-type Ca2+ channels serves as a trigger for further release of Ca2+ from the major intracellular store, the SR. The free cytosolic Ca2+ concentration ([Ca2+]i) determines the extent of activation of contractile proteins …