Iaccarino G, Rockman H A, Shotwell K F, Tomhave E D, Koch W J
Department of Surgery, Duke University Medical Center, Durham North Carolina 27704, USA.
Am J Physiol. 1998 Oct;275(4):H1298-306. doi: 10.1152/ajpheart.1998.275.4.H1298.
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.
通过心脏特异性过表达G蛋白偶联受体激酶3（GRK3）制备转基因小鼠，以探究该GRK在心脏功能中的体内作用。GRK3与β-肾上腺素能受体激酶（β-ARK1）和GRK5一起在心脏中表达。我们之前已经证明，在转基因小鼠中，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）或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）的心肌靶向过表达会导致β-肾上腺素能信号传导和体内心脏功能显著减弱，以及血管紧张素（ANG）II介导的心脏反应选择性脱敏。令人惊讶的是，GRK3的心肌过表达导致通过β-肾上腺素能受体（β-ARs）的正常生化信号传导，并且对β-AR激动剂的体内血流动力学功能与非转基因对照无差异。此外，对ANG II的体内信号传导和功能反应未改变。然而，通过p42/p44丝裂原活化蛋白（MAP）激酶激活评估的心肌凝血酶信号传导在GRK3转基因小鼠心脏中显著减弱，表明GRK3具有独特的体内底物特异性。
