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, JuFang; Song, Jianliang; Gao, Erhe et al. (2014) Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 306:H1066-77|
|Huang, Zheng Maggie; Gao, Erhe; Chuprun, J Kurt et al. (2014) GRK2 in the heart: a GPCR kinase and beyond. Antioxid Redox Signal 21:2032-43|
|Kim, Il-Man; Wang, Yongchao; Park, Kyoung-Mi et al. (2014) *-arrestin1-biased *1-adrenergic receptor signaling regulates microRNA processing. Circ Res 114:833-44|
|Brinks, Henriette; Giraud, Marie-Noelle; Segiser, Adrian et al. (2014) Dynamic patterns of ventricular remodeling and apoptosis in hearts unloaded by heterotopic transplantation. J Heart Lung Transplant 33:203-10|
|Shinozaki, Shohei; Chang, Kyungho; Sakai, Michihiro et al. (2014) Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65. Sci Signal 7:ra106|
|Woodall, Meryl C; Ciccarelli, Michele; Woodall, Benjamin P et al. (2014) G protein-coupled receptor kinase 2: a link between myocardial contractile function and cardiac metabolism. Circ Res 114:1661-70|
|Brady, Donita C; Crowe, Matthew S; Turski, Michelle L et al. (2014) Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 509:492-6|
|Bathgate-Siryk, Ashley; Dabul, Samalia; Pandya, Krunal et al. (2014) Negative impact of *-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms. Hypertension 63:404-12|
|Scimia, Maria Cecilia; Blass, Benjamin E; Koch, Walter J (2014) Apelin receptor: its responsiveness to stretch mechanisms and its potential for cardiovascular therapy. Expert Rev Cardiovasc Ther 12:733-41|
|Weber, C; Neacsu, I; Krautz, B et al. (2014) Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model. Gene Ther 21:131-8|
Showing the most recent 10 out of 103 publications