1. Myocardial overexpression of GRK3 in transgenic mice: evidence for in vivo selectivity of GRKs
- Author
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Walter J. Koch, Eric D. Tomhave, Kyle F. Shotwell, Guido Iaccarino, Howard A. Rockman, Iaccarino, G., Rockman, H. A., Shotwell, K. F., Tomhave, E. D., and Koch, W. J.
- Subjects
G-Protein-Coupled Receptor Kinase 3 ,genetics/metabolism ,Blood Pressure ,Transgenic ,Mice ,Radioligand Assay ,Heart Rate ,Reference Values ,Receptors ,Phosphorylation ,Receptor ,Angiotensin II ,Thrombin ,Heart ,Protein-Serine-Threonine Kinases ,Adenylate Cyclase ,metabolism, Angiotensin II ,pharmacology, Animals, Blood Pressure, Calcium-Calmodulin-Dependent Protein Kinases ,metabolism, Cattle, Cell Membrane ,enzymology, Enzyme Activation, G-Protein-Coupled Receptor Kinase 3, Heart Rate, Heart ,physiology, Hemodynamics ,drug effects, Isoproterenol ,pharmacology, Mice, Mice ,Transgenic, Myocardial Contraction ,drug effects, Myocardium ,enzymology, Open Reading Frames, Peptide Fragments ,pharmacology, Phosphorylation, Protein-Serine-Threonine Kinases, Radioligand Assay, Receptor Protein-Tyrosine Kinases ,genetics/metabolism, Receptors ,Adrenergic ,beta ,physiology, Receptors ,physiology, Reference Values, Rhodopsin ,metabolism, Signal Transduction ,Cell biology ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Adenylyl Cyclases ,Signal Transduction ,Genetically modified mouse ,medicine.medical_specialty ,Rhodopsin ,G protein ,enzymology ,Mice, Transgenic ,Biology ,Protein Serine-Threonine Kinases ,Open Reading Frames ,In vivo ,Physiology (medical) ,Internal medicine ,Receptors, Adrenergic, beta ,medicine ,Animals ,Protein kinase A ,G protein-coupled receptor kinase ,Myocardium ,Cell Membrane ,Hemodynamics ,Isoproterenol ,Receptor Protein-Tyrosine Kinases ,Myocardial Contraction ,Peptide Fragments ,Enzyme Activation ,Endocrinology ,drug effects ,physiology ,Calcium-Calmodulin-Dependent Protein Kinases ,Cattle ,Receptors, Thrombin ,pharmacology ,metabolism - 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 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.
- Published
- 1998