Figure 2. RKIP induces positive inotropy and protects from cell death and diastolic Ca²⁺ leak.

The Raf kinase inhibitor protein (RKIP) binds GRK2 and inhibits G‐protein‐coupled receptor kinase (GRK)‐mediated receptor phosphorylation, which prevents receptor desensitization and internalization and, thus, increases β‐adrenergic receptor signalling. RKIP increases contractility and relaxation of cardiomyocytes via activated β₁‐adrenergic receptor (β₁AR) coupled to stimulatory G‐proteins (G_s): phosphorylated phospholamban (PLN) dissociates from sarco‐/endoplasmatic reticulum Ca²⁺‐ATPase (SERCA2a) and thereby increases SERCA2a activity, Ca²⁺ loading of the sarcoplasmatic reticulum and cardiomyocyte contractility. Phosphorylation of troponin I (TnI) decreases Ca²⁺ sensivity and thereby increases cardiomyocyte relaxation. RKIP mediates anti‐apoptotic, anti‐fibrotic and anti‐arrhythmic effects via increased β₂‐adrenergic receptor (β₂AR) signalling. Continuous signalling of β₂AR coupled to inhibitory G‐proteins (G_i) prevents β₁AR‐stimulated increases in ryanodine receptor 2 (RyR2) and L‐type Ca²⁺ channel (LTCC) phosphorylation and protects from diastolic Ca²⁺ leak.