beta-arrestin-biased signaling through the beta2-adrenergic receptor promotes cardiomyocyte contraction #MMPMID27354517
Carr R 3rd; Schilling J; Song J; Carter RL; Du Y; Yoo SM; Traynham CJ; Koch WJ; Cheung JY; Tilley DG; Benovic JL
Proc Natl Acad Sci U S A 2016[Jul]; 113 (28): E4107-16 PMID27354517show ga
beta-adrenergic receptors (betaARs) are critical regulators of acute cardiovascular physiology. In response to elevated catecholamine stimulation during development of congestive heart failure (CHF), chronic activation of Gs-dependent beta1AR and Gi-dependent beta2AR pathways leads to enhanced cardiomyocyte death, reduced beta1AR expression, and decreased inotropic reserve. beta-blockers act to block excessive catecholamine stimulation of betaARs to decrease cellular apoptotic signaling and normalize beta1AR expression and inotropy. Whereas these actions reduce cardiac remodeling and mortality outcomes, the effects are not sustained. Converse to G-protein-dependent signaling, beta-arrestin-dependent signaling promotes cardiomyocyte survival. Given that beta2AR expression is unaltered in CHF, a beta-arrestin-biased agonist that operates through the beta2AR represents a potentially useful therapeutic approach. Carvedilol, a currently prescribed nonselective beta-blocker, has been classified as a beta-arrestin-biased agonist that can inhibit basal signaling from betaARs and also stimulate cell survival signaling pathways. To understand the relative contribution of beta-arrestin bias to the efficacy of select beta-blockers, a specific beta-arrestin-biased pepducin for the beta2AR, intracellular loop (ICL)1-9, was used to decouple beta-arrestin-biased signaling from occupation of the orthosteric ligand-binding pocket. With similar efficacy to carvedilol, ICL1-9 was able to promote beta2AR phosphorylation, beta-arrestin recruitment, beta2AR internalization, and beta-arrestin-biased signaling. Interestingly, ICL1-9 was also able to induce beta2AR- and beta-arrestin-dependent and Ca(2+)-independent contractility in primary adult murine cardiomyocytes, whereas carvedilol had no efficacy. Thus, ICL1-9 is an effective tool to access a pharmacological profile stimulating cardioprotective signaling and inotropic effects through the beta2AR and serves as a model for the next generation of cardiovascular drug development.
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Proc+Natl+Acad+Sci+U+S+A 2016 ; 113 (28): E4107-16
