Abstract

Stimulation of β‐adrenergic receptors (βARs) provides the most efficient physiological mechanism to enhance contraction and relaxation of the heart. Activation of βARs allows rapid enhancement of myocardial function in order to fuel the muscles for running and fighting in a fight‐or‐flight response. Likewise, βARs become activated during cardiovascular disease in an attempt to counteract the restrictions of cardiac output. However, long‐term stimulation of βARs increases the likelihood of cardiac arrhythmias, adverse ventricular remodelling, decline of cardiac performance and premature death, thereby limiting the use of βAR agonists in the treatment of heart failure. Recently the endogenous Raf kinase inhibitor protein (RKIP) was found to activate βAR 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 β1‐ and β2‐ARs and their downstream targets, the regulation of myocyte calcium cycling and myofilament activity.

Highlights

  • Heart failure occurs if cardiac output is reduced to an extent that it cannot meet the body’s needs

  • Upon phosphorylation by protein kinase C (PKC), Raf kinase inhibitor protein (RKIP) potentiates β-adrenergic receptor (βAR) signalling through inhibition of receptor desensitization, which has proven beneficial effects on myocyte Ca2+ regulation and murine heart failure (Lorenz et al 2003; Schmid et al 2015)

  • In line with β2AR–Gi activation by RKIP, Akt activation was enhanced in RKIP-overexpressing mice and was dependent on β2AR and pertussis toxin-sensitive Gi proteins. These findings suggest that RKIP mediates cell survival via Akt

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Summary

Introduction

Heart failure occurs if cardiac output is reduced to an extent that it cannot meet the body’s needs. Upon phosphorylation by protein kinase C (PKC), RKIP potentiates βAR signalling through inhibition of receptor desensitization, which has proven beneficial effects on myocyte Ca2+ regulation and murine heart failure (Lorenz et al 2003; Schmid et al 2015).

Results
Conclusion

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