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  • CardioExcyte 96

    Combined impedance and MEA-like recordings
  • CardioExcyte 96

    For cardiac safety screening
  • CardioExcyte 96

    Next generation label-free cell analysis
  • CardioExcyte 96

    Intuitive data analysis & arrhythmia detection

2019 - The N-termini of GRK2 and GRK3 simulate the stimulating effects of RKIP on β-adrenoceptors

Icon CE   CardioExcyte 96 publication in Biochemical and Biophysical Research Communications (2019)

Maimari T., Krasel C., Bünemann M., Lorenz K.

Biochemical and Biophysical Research Communications (2019) In Press, Corrected Proof


• RKIP has a well-tolerated positive inotropic effect via β-adrenoceptor activation.

• RKIP binds N-termini of cardiac GRK2 and GRK3 – but not GRK5.

• GRK2/3 N-termini simulate RKIP effects on β-AR signaling by direct receptor interaction.

• Interference strategy using GRK peptides seems to be a promising tool for receptor regulation.


The Raf kinase inhibitor protein (RKIP) activates β-adrenoceptors (β-AR) and thereby induces a well-tolerated cardiac contractility and prevents heart failure in mice. Different to RKIP-mediated β-AR activation, chronic activation of β-AR by catecholamines was shown to be detrimental for the heart. RKIP is an endogenous inhibitor of G protein coupled receptor kinase 2 (GRK2); it binds GRK2 and thereby inhibits GRK2 mediated β-AR phosphorylation and desensitization.

Here, we evaluate RKIP-mediated effects on β-AR to explore new strategies for β-AR modulation. Co-immunoprecipitation assays and pull-down assays revealed subtype specificity of RKIP for the cardiac GRK isoforms GRK2 and GRK3 – not GRK5 – as well as several RKIP binding sites within their N-termini (GRK21−185 and GRK31−185). Overexpression of these N-termini prevented β2-AR phosphorylation and internalization, subsequently increased receptor signaling in HEK293 cells and cardiomyocyte contractility. Co-immunoprecipitation assays of β2-AR with these N-terminal GRK fragments revealed a direct interaction suggesting a steric interference of the fragments with the functional GRK-receptor interaction.

Altogether, N-termini of GRK2 and GRK3 efficiently simulate RKIP effects on β-AR signaling in HEK293 cells and in cardiomyocytes by their binding to β2-AR and, thus, provide important insights for the development of new strategies to modulate β2-AR signaling.

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