Targeting the RH domain of GRK2: potential therapeutic implications in cardiovascular disease

GRK2 is a key regulator of GPCR desensitization through its kinase and RGS homology (RH) domains. Because increased GRK2 activity contribute to cardiovascular diseases, including heart failure, cardiac hypertrophy and hypertension, GRK2 has emerged as an attractive therapeutic target. Most GRK2 inhibitors target its kinase activity, whereas the RH domain has remained largely unexplored. In the present study, we developed novel inhibitors directed against the RH domain of GRK2, characterized them in vitro, and evaluated their effects in cardiovascular physiology of spontaneously hypertensive rats.

We designed GRK2 inhibitors based on the Gα-binding surface within the RH domain of GRK2 and evaluated their ability to dampen RH domain of GRK2 translocation to the plasma membrane by confocal fluorescence imaging and to reduce the interaction between GRK2 and Gαq by co-immunoprecipitation. We also evaluated their effect on second messenger response of GPCRs desensitized by the RH domain of GRK2. Finally, in spontaneously hypertensive rats treated with these inhibitors we evaluated blood pressure, cardiac hypertrophy and fibrosis and assessed their sub-chronic toxicity in healthy rats.

The inhibitors enhanced GPCR response, prevented RH(GRK2) translocation to the plasma membrane, diminished GRK2-Gαq co-immunoprecipitation and reduced desensitization in a concentration-dependent manner. In vivo, they showed efficacy at reducing blood pressure and preventing hypertrophy of spontaneous hypertensive rats with no toxicity under the evaluated conditions.

These findings point to the RH domain targeting as a novel approach to modulate GRK2 function with impact in a model of cardiovascular of disease.