Abstract 1576: A Novel Nuclear Function for GRK5 and Its Potential Role in the Cardiac Hypertrophic Response
G-protein coupled receptor kinases (GRKs) are critical regulators of adrenergic signaling in the heart. During heart failure (HF) GRK2 and GRK5 mRNA, protein, and activity have been shown to be elevated which leads to a diminished cardiac function (CF). Mice overexpressing GRK5 exclusively in the heart have a unique phenotype in response to pressure-overload hypertrophy after aortic banding (TAC) compared to GRK2 overexpressors and non-transgenic littermate controls (NLC). GRK5 mice have significantly decreased CF at 4 weeks post TAC when compared to GRK2 mice and NLCs that have relatively normal CF at this time-point. Moreover, GRK5 mice have significantly less survival 4 weeks post-TAC (18% compared to 45%). Interestingly, GRK5, unlike GRK2 can reside in the nucleus and contains a functional nuclear localization sequence and nuclear export sequence where its function is currently unknown. To begin to address this mechanistically, we treated NLC and GRK5 mice chronically with isoproterenol. Myocytes isolated from GRK5 overexpressors as well as NLC’s have increased GRK5 nuclear localization after one week of isoproterenol treatment with significantly more GRK5 in the nucleus of the transgenic mice. Additionally, the myocytes isolated from the GRK5 transgenic mice had an increase in cell length and no change in cell width while myocytes isolated from NLC mice had no change in cell length and a large increase in width. The changes observed in cell size may represent a switch from concentric hypertrophy for the NLC mice to eccentric hypertrophy for the GRK5 mice. The changes in cell shape and increase in GRK5 nuclear localization may help to explain the differences in CF seen between the GRK5 and NLC mice after TAC. As a result, we have begun to examine novel nuclear targets for GRK5 including histone deactylyases (HDACs). Our preliminary data indicate that nuclear GRK5 has HDAC kinase activity and cause HDAC5 nuclear export. Thus, taken together, our results indicate that GRK5, unlike GRK2 possesses nuclear activity and this elucidates a potential novel mechanism for how GRK5 may be critical in cardiac hypertrophy and HF.