Raf kinase inhibitor protein: lessons of a better way for β-adrenergic receptor activation in the heart

Stimulation of beta-adrenergic receptors (beta ARs) provides themost efficient physiological mechanism to enhance contraction and relaxation of the heart. Activation of beta ARs allows rapid enhancement of myocardial function in order to fuel the muscles for running and fighting in a fight-or-flight response. Likewise, beta ARs become activated during cardiovascular disease in an attempt to counteract the restrictions of cardiac output. However, long-term stimulation of beta ARs increases the likelihood of cardiac arrhythmias, adverse ventricular remodelling, decline of cardiac performance and premature death, thereby limiting the use of beta AR agonists in the treatment of heart failure. Recently the endogenousRaf kinase inhibitor protein (RKIP) was found to activate beta AR signalling of the heart without adverse effects. This review will summarize the current knowledge on RKIP-driven compared to receptor-mediated signalling in cardiomyocytes. Emphasis is given to the differential effects of RKIP on beta(1)- and beta(2)-ARs and their downstream targets, the regulation of myocyte calcium cycling and myofilament activity.