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.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01HL075443-10
Application #
8687712
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
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