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J. Biol. Chem., Vol. 283, Issue 16, 10601-10610, April 18, 2008

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Cardiac-restricted Expression of the Carboxyl-terminal Fragment of GRK3 Uncovers Distinct Functions of GRK3 in Regulation of Cardiac Contractility and Growth

GRK3 CONTROLS CARDIAC ₁-ADRENERGIC RECEPTOR RESPONSIVENESS^*

Leif Erik Vinge¹, Thomas G. von Lueder¹, Ellen Aasum^¶, Eirik Qvigstad^||, Jørgen A. Gravning, Ole-Jakob How^¶, Thor Edvardsen, Reidar Bjørnerheim^**, M. Shakil Ahmed, Birthe W. Mikkelsen, Erik Øie, Toril Attramadal, Tor Skomedal^||, Otto A. Smiseth, Walter J. Koch, Terje S. Larsen^¶, and Håvard Attramadal²

From the Institute for Surgical Research, University of Oslo and Rikshospitalet-Radiumhospitalet Medical Center, Oslo N-0027, Norway, the Department of Cardiology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo N-0027, Norway, the ^¶Department of Medical Physiology, University of Tromsø, N-9037 Tromsø, Norway, the ^||Department of Pharmacology, University of Oslo, N-0316 Oslo, Norway, the ^**Department of Cardiology, Ullevål University Hospital, N-0407 Oslo, Norway, and Center for Translational Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107

G protein-coupled receptor kinase-2 and -3 (GRK2 and GRK3) in cardiac myocytes catalyze phosphorylation and desensitization of different G protein-coupled receptors through specificity controlled by their carboxyl-terminal pleckstrin homology domain. Although GRK2 has been extensively investigated, the function of cardiac GRK3 remains unknown. Thus, in this study cardiac function of GRK3 was investigated in transgenic (Tg) mice with cardiac-restricted expression of a competitive inhibitor of GRK3, i.e. the carboxyl-terminal plasma membrane targeting domain of GRK3 (GRK3ct). Cardiac myocytes from Tg-GRK3ct mice displayed significantly enhanced agonist-stimulated ₁-adrenergic receptor-mediated activation of ERK1/2 versus cardiac myocytes from nontransgenic littermate control (NLC) mice consistent with inhibition of GRK3. Tg-GRK3ct mice did not display alterations of cardiac mass or left ventricular dimensions compared with NLC mice. Tail-cuff plethysmography of 3- and 9-month-old mice revealed elevated systolic blood pressure in Tg-GRK3ct mice versus control mice (3-month-old mice, 136.8 ± 3.6 versus 118.3 ± 4.7 mm Hg, p < 0.001), an observation confirmed by radiotelemetric recording of blood pressure of conscious, unrestrained mice. Simultaneous recording of left ventricular pressure and volume in vivo by miniaturized conductance micromanometry revealed increased systolic performance with significantly higher stroke volume and stroke work in Tg-GRK3ct mice than in NLC mice. This phenotype was corroborated in electrically paced ex vivo perfused working hearts. However, analysis of left ventricular function ex vivo as a function of increasing filling pressure disclosed significantly reduced (dP/dt)_min and prolonged time constant of relaxation () in Tg-GRK3ct hearts at elevated supraphysiological filling pressure compared with control hearts. Thus, inhibition of GRK3 apparently reduces tolerance to elevation of preload. In conclusion, inhibition of cardiac GRK3 causes hypertension because of hyperkinetic myocardium and increased cardiac output relying at least partially on cardiac myocyte ₁-adrenergic receptor hyper-responsiveness. The reduced tolerance to elevation of preload may cause impaired ability to withstand pathophysiological mechanisms of heart failure.

Received for publication, October 30, 2007

^* This work was supported by grants from the Norwegian Research Council, the Norwegian Council on Cardiovascular Disease, and Center for Heart Failure Research, Faculty of Medicine, University of Oslo. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Institute for Surgical Research, A3.1013, Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway. Tel.: 47-23073520; Fax: 47-23073530; E-mail: havard.attramadal{at}medisin.uio.no.

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