| First Author | Maimari T | Year | 2019 |
| Journal | Biochem Biophys Res Commun | Volume | 520 |
| Issue | 2 | Pages | 327-332 |
| PubMed ID | 31604529 | Mgi Jnum | J:291827 |
| Mgi Id | MGI:6443718 | Doi | 10.1016/j.bbrc.2019.09.135 |
| Citation | Maimari T, et al. (2019) The N-termini of GRK2 and GRK3 simulate the stimulating effects of RKIP on beta-adrenoceptors. Biochem Biophys Res Commun 520(2):327-332 |
| abstractText | The Raf kinase inhibitor protein (RKIP) activates beta-adrenoceptors (beta-AR) and thereby induces a well-tolerated cardiac contractility and prevents heart failure in mice. Different to RKIP-mediated beta-AR activation, chronic activation of beta-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 beta-AR phosphorylation and desensitization. Here, we evaluate RKIP-mediated effects on beta-AR to explore new strategies for beta-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 (GRK2(1-185) and GRK3(1-185)). Overexpression of these N-termini prevented beta2-AR phosphorylation and internalization, subsequently increased receptor signaling in HEK293cells and cardiomyocyte contractility. Co-immunoprecipitation assays of beta2-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 beta-AR signaling in HEK293cells and in cardiomyocytes by their binding to beta2-AR and, thus, provide important insights for the development of new strategies to modulate beta2-AR signaling. |
