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Am J Physiol Heart Circ Physiol 275: H1298-H1306, 1998;
0363-6135/98 $5.00
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Vol. 275, Issue 4, H1298-H1306, October 1998

Myocardial overexpression of GRK3 in transgenic mice: evidence for in vivo selectivity of GRKs

Guido Iaccarino1,2, Howard A. Rockman3, Kyle F. Shotwell1, Eric D. Tomhave1, and Walter J. Koch1

Departments of 1 Surgery and 2 Medicine, Duke University Medical Center, Durham 27710; and 3 Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27704

Transgenic mice were generated with cardiac-specific overexpression of the G protein-coupled receptor kinase 3 (GRK3) to explore the in vivo role of this GRK in cardiac function. GRK3 is expressed in the heart along with the beta -adrenergic receptor kinase (beta -ARK1) and GRK5. We have previously demonstrated that myocardial-targeted overexpression in transgenic mice of beta -ARK1 (Koch, W.J., H. A. Rockman, P. Samama, R. A. Hamilton, R. A. Bond, C. A. Milano, and R. J. Lefkowitz. Science 268: 1350-1353, 1995) or GRK5 (Rockman, H.A., D.-J. Choi, N. U. Rahman, S. A. Akhter, R. J. Lefkowitz, and W. J. Koch. Proc. Natl. Acad. Sci. USA 93: 9954-9959, 1996) results in significant attenuation of beta -adrenergic signaling and in vivo cardiac function and selective desensitization of angiotensin (ANG) II-mediated cardiac responses. Surprisingly, myocardial overexpression of GRK3 resulted in normal biochemical signaling through beta -adrenergic receptors (beta -ARs), and in vivo hemodynamic function in response to a beta -AR agonist was indistinguishable from that in nontransgenic controls. Furthermore, in vivo signaling and functional responses to ANG II were unaltered. However, myocardial thrombin signaling, as assessed by p42/p44 mitogen-activated protein (MAP) kinase activation, was significantly attenuated in GRK3 transgenic mouse hearts, indicating a distinct in vivo substrate specificity for GRK3.

beta -adrenergic receptor; thrombin receptor; G protein signaling; desensitization; cardiac contractility


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