The G protein-coupled receptor (GPCR) kinases (GRKs) are a family of serine/threonine kinases that phosphorylate and desensitize agonist-occupied GPCRs. Two members, GRK2 and GRK5, are abundant in the heart, and their abundance is increased during heart failure and other instances of cardiac pathology. GRK5 differs from GRK2 in possessing a nuclear localization sequence (NLS). Martini et al. investigated the role of GRK5 in cardiac pathology in transgenic mice (TgGRK5) that have an overabundance of GRK5 in cardiomyocytes. The authors performed transverse aortic constriction (TAC) to induce a hypertrophic response, which is characterized by a gradual increase in heart mass followed by heart failure. TgGRK5 mice had an increased hypertrophic response after 4 weeks of TAC compared with that of control mice. Immunofluorescence and Western blotting analyses showed that TAC increased the proportion of nuclear-localized GRK5 compared with that in unstressed TgGRK5 mice. Transgenic mice expressing a mutant form of GRK5 that lacked an NLS were no different from control mice in their hypertrophic response to TAC. Reporter assays showed that nuclear accumulation of GRK5 was associated with the increased activity of myocyte enhancer factor-2 (MEF2), a transcription factor important in driving the hypertrophic response. In myocytes, GRK5 coimmunoprecipitated with a tagged form of histone deacetylase 5 (HDAC5), a repressor of MEF2 activity. GRK5 phosphorylated tagged HDAC5 in COS-7 cells, which resulted in the nuclear export of HDAC5. In TgGRK5 mice, TAC increased the association between GRK5 and HDAC5. Together, these data suggest that GRK5 acts as a HDAC kinase to regulate gene expression in addition to its traditional role in inhibiting GPCR signaling.
J. S. Martini, P. Raake, L. E. Vinge, B. DeGeorge Jr., J. K. Chuprun, D. M. Harris, E. Gao, A. D. Eckhart, J. A. Pitcher, W. J. Koch, Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. Proc. Natl. Acad. Sci. U.S.A. 105, 12457-12462 (2008). [Abstract] [Full Text]