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PNAS 105 (34): 12457-12462

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes

Jeffrey S. Martini, Philip Raake, Leif E. Vinge, Brent R. DeGeorge, Jr., J. Kurt Chuprun, David M. Harris, Erhe Gao, Andrea D. Eckhart, Julie A. Pitcher, and Walter J. Koch

*George Zallie and Family Laboratory for Cardiovascular Gene Therapy and {dagger}Eugene Feiner Laboratory for Vascular Biology and Thrombosis, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107; and {ddagger}Medical Research Council Laboratory for Molecular Cell Biology and Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom

Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved June 3, 2008

Received for publication March 31, 2008.

Abstract: G protein-coupled receptor (GPCR) kinases (GRKs) are critical regulators of cellular signaling and function. In cardiomyocytes, GRK2 and GRK5 are two GRKs important for myocardial regulation, and both have been shown to be up-regulated in the dysfunctional heart. We report that increased levels and activity of GRK5 in failing myocardium may have unique significance due to its nuclear localization, a property not shared by GRK2. We find that transgenic mice with elevated cardiac GRK5 levels have exaggerated hypertrophy and early heart failure compared with control mice after pressure overload. This pathology is not present in cardiac GRK2-overexpressing mice or in mice with overexpression of a mutant GRK5 that is excluded from the nucleus. Nuclear accumulation of GRK5 is enhanced in myocytes after aortic banding in vivo and in vitro in myocytes after increased G{alpha}q activity, the trigger for pressure-overload hypertrophy. GRK5 enhances activation of MEF2 in concert with Gq signals, demonstrating that nuclear localized GRK5 regulates gene transcription via a pathway critically linked to myocardial hypertrophy. Mechanistically, we show that this is due to GRK5 acting, in a non-GPCR manner, as a class II histone deacetylase (HDAC) kinase because it can associate with and phosphorylate the myocyte enhancer factor-2 repressor, HDAC5. Moreover, significant HDAC activity can be found with GRK5 in the heart. Our data show that GRK5 is a nuclear HDAC kinase that plays a key role in maladaptive cardiac hypertrophy apparently independent of any action directly on GPCRs.

Key Words: cardiac hypertrophy • G protein signaling • heart failure • myocyte signaling

Author contributions: J.S.M., D.M.H., A.D.E., J.A.P., and W.J.K. designed research; J.S.M., P.R., L.E.V., B.D., and E.G. performed research; J.S.M. and D.M.H. contributed new reagents/analytic tools; J.S.M., B.D., J.K.C., D.M.H., A.D.E., and W.J.K. analyzed data; and J.S.M. and W.J.K. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0803153105/DCSupplemental.

§To whom correspondence should be addressed. E-mail: walter.koch{at}jefferson.edu

© 2008 by The National Academy of Sciences of the USA

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