GRK5's catalytic activity in regulating basal and stressed cardiac function has not been studied. Herein, we studied knock-in mice in which GRK5 was mutated to render it catalytically inactive (K215R). At baseline, GRK5-K215R mice showed a marked decline in cardiac function with increased apoptosis and fibrosis. In vitro, restriction of GRK5 inside the nucleus of cardiomyocytes resulted in enhanced cell death along with higher p53 levels. Moreover, in fibroblasts, we demonstrated that K215R mutation promoted the transition into myofibroblast phenotype. This study provides novel insight into the biological actions of GRK5, that are essential for its future targeting.
Keywords: DNA; GPCR, G protein-coupled receptor; GRK; GRK5, G protein-coupled receptor kinase 5; HDAC5, histone deacetylase 5; K215R, lysine 215 arginine; LV, left ventricular; NES, nuclear export signal; NLS, nuclear localization signal; PIF, pifithrin; SMA, smooth muscle actin; apoptosis; cardiac; nuclear.
© 2022 The Authors.