title: Ca(2+) signaling in the myocardium by (redox) regulation of PKA/CaMKII.
abstract: Homeostatic cardiac function is maintained by a complex network of interdependent signaling pathways which become compromised during disease progression. Excitation-contraction-coupling, the translation of an electrical signal to a contractile response is critically dependent on a tightly controlled sequence of events culminating in a rise in intracellular Ca(2+) and subsequent contraction of the myocardium. Dysregulation of this Ca(2+) handling system as well as increases in the production of reactive oxygen species (ROS) are two major contributing factors to myocardial disease progression. ROS, generated by cellular oxidases and by-products of cellular metabolism, are highly reactive oxygen derivatives that function as key secondary messengers within the heart and contribute to normal homeostatic function. However, excessive production of ROS, as in disease, can directly interact with kinases critical for Ca(2+) regulation. This post-translational oxidative modification therefore links changes in the redox status of the myocardium to phospho-regulated pathways essential for its function. This review aims to describe the oxidative regulation of the Ca(2+)/calmodulin-dependent kinase II (CaMKII) and cAMP-dependent protein kinase A (PKA), and the subsequent impact this has on Ca(2+) handling within the myocardium. Elucidating the impact of alterations in intracellular ROS production on Ca(2+) dynamics through oxidative modification of key ROS sensing kinases, may provide novel therapeutic targets for preventing myocardial disease progression.
authors: Heart Research Center Goettingen, Clinic of Cardiology and Pulmonology, University Medical Center Goettingen Goettingen, Germany.
authors: Alex S
authors: AS
authors: Johnston
authors: Heart Research Center Goettingen, Clinic of Cardiology and Pulmonology, University Medical Center Goettingen Goettingen, Germany ; German Center for Cardiovascular Research (DZHK) site Göttingen Berlin, Germany.
authors: Stephan E
authors: SE
authors: Lehnart
authors: Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, King's College London, St. Thomas' Hospital London, UK.
authors: Joseph R
authors: JR
authors: Burgoyne
keywords: Ca2+ signaling; CaMKII; PKA; cardiac contractility; redox signaling