Myocardial overexpression of GRK3 in transgenic mice: evidence for in vivo selectivity of GRKs.
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.
Iaccarino
G
G
Department of Surgery, Duke University Medical Center, Durham North Carolina 27704, USA.
Rockman
H A
HA
Shotwell
K F
KF
Tomhave
E D
ED
Koch
W J
WJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002417:Cattle; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D054770:G-Protein-Coupled Receptor Kinase 3; D006321:Heart / Q000502:physiology*; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D016366:Open Reading Frames; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011869:Radioligand Assay; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D018179:Receptors, Thrombin / Q000502:physiology; D012016:Reference Values; D012243:Rhodopsin / Q000378:metabolism; D015398:Signal Transduction
D010446:Peptide Fragments; D011943:Receptors, Adrenergic, beta; D018179:Receptors, Thrombin; C082835:thrombin receptor peptide (42-47); D000804:Angiotensin II; D012243:Rhodopsin; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D054770:G-Protein-Coupled Receptor Kinase 3; C517850:GRK3 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol