The contractile and neurohormonal roles of phospholamban in heart failure

Heart failure is a down-spiraling syndrome of neurohormonal imbalance and hemodynamic instability, in which impaired cardiac function has been linked to perturbations in subcellular calcium handling. Phospholamban (PLB) is a phosphoprotein that inhibits cardiac muscle relaxation by lowering the apparent affinity of the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2) for Ca2+. Major determinants of phospholamban's regulatory activity are the relative PLB/SERCA2 ratio and phospholamban's phosphorylation status, both of which are altered in failing human hearts. PLB impairs myocardial calcium handling and observed perturbations of PLB levels and/or activity in human heart failure may contribute to depressed contractility. Therapeutic implications for PLB are intriguing, as PLB's activity and levels are significantly influenced by specific neurohormonal systems.