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.
|Wang, Jialu; Hanada, Kenji; Gareri, Clarice et al. (2018) Mechanoactivation of the angiotensin II type 1 receptor induces ?-arrestin-biased signaling through G?i coupling. J Cell Biochem 119:3586-3597|
|Hayashi, Hiroki; Hess, Douglas T; Zhang, Rongli et al. (2018) S-Nitrosylation of ?-Arrestins Biases Receptor Signaling and Confers Ligand Independence. Mol Cell 70:473-487.e6|
|Rizza, Salvatore; Cardaci, Simone; Montagna, Costanza et al. (2018) S-nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy. Proc Natl Acad Sci U S A 115:E3388-E3397|
|Cannavo, Alessandro; Koch, Walter J (2018) GRK2 as negative modulator of NO bioavailability: Implications for cardiovascular disease. Cell Signal 41:33-40|
|Wang, Jialu; Gareri, Clarice; Rockman, Howard A (2018) G-Protein-Coupled Receptors in Heart Disease. Circ Res 123:716-735|
|Kim, Jihee; Grotegut, Chad A; Wisler, James W et al. (2018) ?-arrestin 1 regulates ?2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility. Skelet Muscle 8:39|
|Zhou, Hua-Lin; Stomberski, Colin T; Stamler, Jonathan S (2018) Cross Talk Between S-Nitrosylation and Phosphorylation Involving Kinases and Nitrosylases. Circ Res 122:1485-1487|
|de Lucia, Claudio; Gambino, Giuseppina; Petraglia, Laura et al. (2018) Long-Term Caloric Restriction Improves Cardiac Function, Remodeling, Adrenergic Responsiveness, and Sympathetic Innervation in a Model of Postischemic Heart Failure. Circ Heart Fail 11:e004153|
|Grisanti, Laurel A; Schumacher, Sarah M; Tilley, Douglas G et al. (2018) Designer Approaches for G Protein-Coupled Receptor Modulation for Cardiovascular Disease. JACC Basic Transl Sci 3:550-562|
|de Lucia, Claudio; Eguchi, Akito; Koch, Walter J (2018) New Insights in Cardiac ?-Adrenergic Signaling During Heart Failure and Aging. Front Pharmacol 9:904|
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