Increased cardiac contractility during acute stress is largely mediated by ?-adrenergic receptors (AR). In contrast, angiotensin (AT1) receptors appear to play the major role in cardiac adaptation to chronic hemodynamic stress. Both ?-AR and AT1 receptors are members of the superfamily of G protein-coupled receptors that are desensitized via activation-dependent phosphorylation by G protein-coupled receptor kinases (GRKs). Emerging data in cell-based systems suggest that, concurrent with desensitization of G protein signaling, GRK phosphorylation of receptors can initiate non-G protein signaling through MAP/SAP kinases. Importantly, GRK2 is postulated to be a pathological mediator of heart failure, and our studies show that a common genetic polymorphism of GRKS can determine therapeutic efficacy of p-AR blockade in African Americans with heart failure. Of the seven mammalian GRKs, GRK2 and GRKS are most highly expressed in the heart, and can modulate both ?-AR and AT1. Because deletion of the GRK2 gene results in embryonic lethality, the relative physiological importance of these two GRKs as regulators of acute and chronic cardiac adaptive responses is unclear. Thus, to better understand the roles of GRK2 and GRKS on ?-AR and AT1 signaling pathways during acute or chronic cardiac stress, we have generated mice in which GRK2 can be conditionally ablated using Cre-lox technology. While germ-line deletion with Ella-Cre was lethal, cardiac-myocyte specific deletion with Nkx2.5-Cre resulted in viable mice suitable for study. Additionally we have obtained GRKS loxP mice, and are generating the dual cardiac GRK2/GRK5 knockouts. Using these and other model systems we propose the following Specific Aims: SA#1-Delineate the individual modulatory effects of GRK2 and GRKS on the cardiac inotropic response to catecholamines and angiotensin II. SA#2-Elucidate the effects of GRK2 and GRKS on cardiac MAPkinase and SAPkinase signaling through the ?-AR and AT1 receptor pathways. SA#3-Define the signaling functions of GRK2 and GRKS during embryonic development. Our studies will use state-of-the art analytical techniques of genetic manipulation and micro-physiological analysis in cell-based systems and the in vivo mouse heart to provide insight into the roles of GRK-mediated signal modulation in cardiac stress-responses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087871-05
Application #
7862452
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$477,434
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Franco, Antonietta; Zhang, Lihong; Matkovich, Scot J et al. (2018) G-protein receptor kinases 2, 5 and 6 redundantly modulate Smoothened-GATA transcriptional crosstalk in fetal mouse hearts. J Mol Cell Cardiol 121:60-68
Dorn 2nd, Gerald W (2016) Canon Fodder-A Case for Contrarian Science. Circ Res 119:584-6
Dorn 2nd, Gerald W (2016) Central Parkin: The evolving role of Parkin in the heart. Biochim Biophys Acta 1857:1307-1312
Dorn 2nd, Gerald W (2015) Cardiac regeneration - Alchemy, science, and a wee bit of magic? J Mol Cell Cardiol 81:10-1
Shirihai, Orian S; Song, Moshi; Dorn 2nd, Gerald W (2015) How mitochondrial dynamism orchestrates mitophagy. Circ Res 116:1835-49
Westenbrink, B Daan; Ling, Haiyun; Divakaruni, Ajit S et al. (2015) Mitochondrial reprogramming induced by CaMKII? mediates hypertrophy decompensation. Circ Res 116:e28-39
Song, Moshi; Gong, Guohua; Burelle, Yan et al. (2015) Interdependence of Parkin-Mediated Mitophagy and Mitochondrial Fission in Adult Mouse Hearts. Circ Res 117:346-51
Song, Moshi; Matkovich, Scot J; Zhang, Yan et al. (2015) Combined cardiomyocyte PKC? and PKC? gene deletion uncovers their central role in restraining developmental and reactive heart growth. Sci Signal 8:ra39
Dorn 2nd, Gerald W (2013) Mitochondrial dynamism and cardiac fate--a personal perspective. Circ J 77:1370-9
Ciccarelli, Michele; Sorriento, Daniela; Franco, Antonietta et al. (2013) Endothelial G protein-coupled receptor kinase 2 regulates vascular homeostasis through the control of free radical oxygen species. Arterioscler Thromb Vasc Biol 33:2415-24

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