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

Guido Iaccarino, Howakd A. Rockman, Kyle F. Shotwell, Eric D. Tomhave, Walter J. Koch

Research output: Contribution to journalArticle

Abstract

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 β-adrenergic receptor kinase (β-ARK1) and GRK5. We have previously demonstrated that myocardial-targeted overexpression in transgenic mice of β-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 β-adrenergic signaling and in vive cardiac function and selective desensitization of angiotensin (ANG) II-mediated cardiac responses. Surprisingly, myocardial overexpression of GRK3 resulted in normal biochemical signaling through β-adrenergic receptors (β-ARs), and in vivo hemodynamic function in response to a β-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.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume275
Issue number4 44-4
Publication statusPublished - 1998

Keywords

  • β-Adrenergic receptor
  • Cardiac contractility
  • Desensitization
  • G protein signaling
  • Thrombin receptor

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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