B-arrestins are multifunctional proteins that are recruited to G protein-coupled receptors (GCPRs) following agonist stimulation. While the classical role of (3-arrestin is to mediate receptor desensitization, work by investigators of this PPG have recently shown that P-arrestin can stimulate signaling in the absence of classical G protein activation. The existence of B-arrestin-mediated signaling independent of G proteins requires that receptors adopt multiple """"""""active"""""""" conformations or """"""""ligand selective states"""""""". The ability of unique ligand-receptor conformations to promote preferential B-arrestin signaling is an emerging concept known as """"""""biased signaling"""""""". The molecular mechanisms that underlie p-an-estin-biased signaling for the p-adrenergic receptor of (PAR), and its physiological consequences in the heart, are not known. In this proposal, we will test the hypothesis that mutant p i - and P2 can be engineered that will selectively stimulate p-arrestinbiased signaling independent of G protein activation, and that p-arrestin-biased signaling will promote cardiomyocyte cell survival to limit the development of heart failure in response to pathological stimuli. Accordingly, the specific aims of the study are:
Aim 1 : To engineerBp1 AR mutants that show selective bias for p-arrestin recruitment.
Aim 2 : To identify the mechanism of activation and signaling pathways activated by P1AR and B2AR mutants in the absence of G protein activation.
Aim 3 : To test in adult cardiomyocytes whether p-arrestin-biasedBP2AR TYY and B1 AR mutants activate cardioprotective signaling in response to agonist stimulation and ischemia.
Aim 4 : To test in vivo whether the B-arrestin-biased Bp2AR TYY and pi AR mutant activities cardioprotective pathways under conditions of pathological stress. By exploring these aims, we will define the pathways by which G protein-Independent activation of BARs may lead to stimulation of cardioprotective signaling. If our hypothesis is correct, we will show that ligandstimulated PARS, which selectively activate B-arrestin signaling pathways, are cardioprotecitve. Since, by definition, the administration of a ligand that does not stimulate G protein signaling is B-blackade, we will have demonstrated proof-of concept for the development of an entirely novel class of receptor blockers. We believe these data will provide considerable impetus for the development of novel p-arrestin-biased therapeutic agents to treat human heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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Duke University
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Cannavo, Alessandro; Rengo, Giuseppe; Liccardo, Daniela et al. (2017) ?1-Blockade Prevents Post-Ischemic Myocardial Decompensation Via ?3AR-Dependent Protective Sphingosine-1 Phosphate Signaling. J Am Coll Cardiol 70:182-192
Schumacher, Sarah M; Koch, Walter J (2017) Noncanonical Roles of G Protein-coupled Receptor Kinases in Cardiovascular Signaling. J Cardiovasc Pharmacol 70:129-141
Lai, Thung-S; Lindberg, Robert A; Zhou, Hua-Lin et al. (2017) Endothelial cell-surface tissue transglutaminase inhibits neutrophil adhesion by binding and releasing nitric oxide. Sci Rep 7:16163
Waldschmidt, Helen V; Homan, Kristoff T; Cato, Marilyn C et al. (2017) Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine. J Med Chem 60:3052-3069
Eisner, Verónica; Cupo, Ryan R; Gao, Erhe et al. (2017) Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity. Proc Natl Acad Sci U S A 114:E859-E868
Bouley, Renee; Waldschmidt, Helen V; Cato, M Claire et al. (2017) Structural Determinants Influencing the Potency and Selectivity of Indazole-Paroxetine Hybrid G Protein-Coupled Receptor Kinase 2 Inhibitors. Mol Pharmacol 92:707-717
Jean-Charles, Pierre-Yves; Yu, Samuel Mon-Wei; Abraham, Dennis et al. (2017) Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of ?-adrenergic receptor signaling. JCI Insight 2:
Elphinstone, Robyn E; Besla, Rickvinder; Shikatani, Eric A et al. (2017) S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria. Infect Immun 85:
Waldschmidt, Helen V; Homan, Kristoff T; Cruz-Rodríguez, Osvaldo et al. (2016) Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors. J Med Chem 59:3793-807
Zhang, Rongli; Hess, Douglas T; Reynolds, James D et al. (2016) Hemoglobin S-nitrosylation plays an essential role in cardioprotection. J Clin Invest 126:4654-4658

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