Abstract 336: A Novel Nuclear Function for GRK5 and Its Potential Role in the Hypertrophic Response
G protein-coupled receptor kinases (GRKs) are critical regulators of adrenergic signaling in the heart. During heart failure (HF) GRK2 and GRK5 protein are elevated, leading to a diminished cardiac function. Mice with cardiac-specific overexpression of GRK5 have a unique phenotype in response to overload hypertrophy. GRK5 mice, but not GRK2 overexpressors or non-transgenic control (NLC) mice, rapidly decompensate within 4 weeks after aortic banding (TAC) with signs of HF. There is also a heightened hypertrophic response preceding HF including increased expression of fetal genes. GRK5, unlike GRK2 can reside in the nucleus and contains a nuclear localization (NLS) and export sequence (NES). Our hypothesis is that cardiac decompensation after TAC in GRK5 mice is due to its unique activity in the nucleus. Histone deacetylases (HDAC) reside in the nucleus and act as transcriptional repressors of cardiac hypertrophy at the level of MEF2. Phosphorylation of HDACs results in their nuclear export and activation of hypertrophic gene transcription. We have found that nuclear GRK5 can phosphorylate HDAC5 and associates with HDAC5 in myocytes. Moreover, significant HDAC activity can be found after immunoprecipitation of GRK5 from mouse hearts showing in vivo relevance of this interaction. We also found in vitro that nuclear export of HDAC5 can be induced when co-transfected with a nuclear form of GRK5 (GRK5 Δ NES). Pressure-overload hypertrophy is triggered by Gq activation and we found that expression a constitutively active mutant Gαq in myocytes leads to significant GRK5 nuclear translocation and Gαq and GRK5 overexpression enhances MEF2 activity and hypertrophy in myocytes. Finally, in vivo HDAC activity associated with GRK5 is increased after TAC. Our results indicate that GRK5 possesses nuclear HDAC kinase activity and this novel non-G protein-coupled receptor activity of this GRK may play a key role in maladaptive cardiac hypertrophy and progression to HF. This is clinically relevant since cardiac GRK5 has been found to be increased in human HF patients.