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Beta-Arrestin-Mediated Signaling in the Heart

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Beta-Arrestin-Mediated Signaling in the Heart SPECIAL ARTICLE Circ J 2008; 72: 1725–1729 Beta-Arrestin-Mediated Signaling in the Heart Priyesh A. Patel, BS; Douglas G. Tilley, PhD*; Howard A. Rockman, MD*,** Beta-arrestin is a multifunctional adapter protein well known for its role in G-protein-coupled receptor (GPCR) desensitization. Exciting new evidence indicates thatβ-arrestin is also a signaling molecule capable of initiating its own G-protein-independent signaling at GPCRs. One of the best-studiedβ-arrestin signaling pathways is the one involvingβ-arrestin-dependent activation of a mitogen-activated protein kinase cascade, the extracellular regulated kinase (ERK). ERK signaling, which is classically activated by agonist stimulation of the epidermal growth factor receptor (EGFR), can be activated by a number of GPCRs in aβ-arrestin-dependent manner. Recent work in animal models of heart failure suggests thatβ-arrestin-dependent activation of EGFR/ERK signaling by theβ-1-adrenergic receptor, and possibly the angiotensin II Type 1A receptor, are cardioprotective. Hence, a new model of signaling at cardiac GPCRs has emerged and implicates classical G-protein-mediated signaling with promoting harmful remodeling in heart failure, while concurrently linkingβ-arrestin-dependent, G-protein-inde- pendent signaling with cardioprotective effects. Based on this paradigm, a new class of drugs could be identified, termed “biased ligands”, which simultaneously block harmful G-protein signaling, while also promoting cardio- protectiveβ-arrestin-dependent signaling, leading to a potential breakthrough in the treatment of chronic cardiac disease. (Circ J 2008; 72: 1725–1729) Key Words: Beta-arrestin; Beta-1-adrenergic receptor; Extracellular regulated kinase (ERK); G protein- coupled receptor -protein-coupled receptors (GPCR) are ubiquitously Beta-Arrestin as a Desensitizing expressed, 7-transmembrane spanning receptors and Signaling Molecule G that regulate a vast multitude of physiologic proc- esses.1 The classic paradigm is that agonist stimulation of a Desensitization GPCR activates a receptor-associated G protein to promote Beta-arrestin exists as 2 isoforms, β-arrestin1 and β- downstream signaling via generation of second messengers.1 arrestin2, both of which are important in the regulation of Termination of GPCR signaling occurs by a process known GPCR signaling. It has long been known that β-arrestins as desensitization,2 which involves phosphorylation of the prevent G protein signaling by physically uncoupling the activated receptor by a GPCR kinase and subsequent recruit- interaction between a GPCR and its associated G protein.1,3 ment of the multifunctional adapter proteinβ-arrestin. The Moreover, recent studies of the β-2-adrenergic receptor β-arrestin in turn physically uncouples the G protein from (β2AR) and the muscarinic M1 receptor show thatβ-arres- the receptor, effectively terminating signaling.1,3 Although tins directly promote degradation of second messengers via the role ofβ-arrestin in desensitization is well established, recruitment of phosphodiesterase and diacylglycerol kinase recent evidence indicates thatβ-arrestin is far more func- respectively, hinting at a more elegant and versatile role for tionally versatile than previously appreciated.1,3 β-arrestins in desensitization than previously understood.5,6 Perhaps the most important discovery in the past decade In addition to their role in desensitization, bothβ-arrestin1 is the ability ofβ-arrestin to facilitate trafficking of the re- andβ-arrestin2 are intricately involved in GPCR trafficking, ceptor and initiate cell signaling events in its own right, recycling, and degradation following agonist stimulation independent of G protein activation. This new paradigm (reviewed by Moore et al3). establishes that, while agonist stimulation of a GPCR leads to immediate G-protein-mediated signaling,β-arrestin itself Signaling promotes a second wave of β-arrestin-dependent, G-pro- Although β-arrestins indirectly alter signaling through tein-independent signaling.1,3,4 Here we present evidence their roles in receptor desensitization and trafficking, new highlighting the importance of distinguishing the discrete data show that they can initiate signaling independent of G physiologic outcomes ofβ-arrestin-dependent vs G-protein- protein activation. The best studied example of aβ-arrestin- dependent signaling at GPCRs. activated signaling pathway is the extracellular regulated kinase (ERK) cascade. ERK signaling is prototypically activated by growth factor stimulation of receptor tyrosine (Received August 1, 2008; accepted August 1, 2008; released online 7 October 7, 2008) kinases (RTKs). However, recent studies have shown that School of Medicine, *Department of Medicine and **Department of several GPCRs can themselves initiate ERK signaling by Cell Biology and Genetics, Duke University, Durham, NC, USA both G-protein- andβ-arrestin-dependent processes. Exam- Mailing address: Howard A. Rockman, MD, Department of Medicine, ples of such receptors include the angiotensin II Type 1A Duke University Medical Center, DUMC 3104, 226 CARL Building, receptor (AT1AR),8β-1-adrenergic receptor (β1AR),9β2AR,10 Research Drive, Durham, NC 27710, USA. E-mail: h.rockman@ vasopressin V2 receptor11 and parathyroid hormone recep- duke.edu Supported by grants from the National Institutes of Health 12 to HAR (HL56687 and HL75443) tor. Interestingly, the time course and molecular conse- All rights are reserved to the Japanese Circulation Society. For per- quences of activating ERK signaling through G-protein- missions, please e-mail: [email protected] mediated pathways vs β-arrestin-mediated pathways are Circulation Journal Vol.72, November 2008 1726 PATEL PA et al. Fig1. Theβ-arrestin-dependent and G-protein-de- pendent pathways differentially activate extracellular regulated kinase (ERK) signaling. The angiotensin II Type 1A receptor (AT1AR) is a Gq coupled receptor that can activate ERK signaling by both G-protein- andβ-arrestin-dependent processes. Upon angioten- sin II stimulation, inhibition ofβ-arrestin signaling by the AT1AR usingβ-arrestin2 siRNA reveals that Gq promotes rapid, short-lived activation of ERK (blue line). In contrast,β-arrestin mediates a late, extended phase of ERK activation as seen by PKC inhibition of Gq signaling (orange line). Inhibiting both G protein and β-arrestin-signaling prevents ERK activation (green line), suggesting that the AT1AR cannot acti- vate ERK in a manner independent of G protein orβ- arrestin. PKC, protein kinase C; CTL, control siRNA. Printed with permission from Science 2005; 308: 512–517 and J Biol Chem 2004; 279: 35518–35525. Fig2. Theβ-1-adrenergic receptor (β1AR)-mediated transactivation of epidermal growth factor receptor (EGFR) isβ- arrestin dependent. HEK293 cells stably overexpressing wild-typeβ1AR were transiently transfected with EGFR-GFP and eitherβ-arrestin si-RNA or control si-RNA. After treatment with theβ1AR agonist dobutamine (Dob), EGFR redis- tributed into cellular aggregates, thereby indicating activation of the EGFR (panel 2, arrowheads). Redistribution of the EGFR into aggregates was prevented in the presence ofβ-arrestin siRNA, in which case EGFR remained localized to the plasma membrane (panel 5, arrow). Taken together, these findings indicate thatβ-arrestin is necessary forβ1AR-mediated transactivation of the EGFR. ICI, ICI118551, a selectiveβ-2-adrenergic receptor blocker; IB, immunoblot; EGF, epidermal growth factor; GFP, green fluorescent protein. Adapted with permission from J Clin Invest 2007; 117: 2445–2458. quite different. For example, in HEK293 cells overexpress- creasingly been investigated in order to uncover the cross- ing the AT1AR, G protein activation leads to peak activity talk between the GPCR and RTK signaling pathways. ERK within 2min and promotes both nuclear and cytoplasmic signaling is classically activated by agonist stimulation of localization of activated ERK. In contrast,β-arrestin-medi- RTKs, an example being the epidermal growth factor recep- ated signaling following angiotensin II stimulation of tor (EGFR). EGFR initiates a signaling cascade consisting AT1AR has a slower and more prolonged pattern and of Raf, MEK, and ERK, as well as recruitment of several promotes only cytoplasmic ERK localization (Fig1).13 In adapter and scaffolding proteins, including Src, Grb2 and addition, G-protein-mediated nuclear localization of ERK Ras, to promote mitogenic and anti-apoptotic effects.7,15 promotes increased transcription of early growth response 1, Anti-apoptotic signaling can be initiated through ERK phos- indicating that only G-protein-dependent signaling promotes phorylation of Bad, thereby allowing homodimerization of transcriptional events.8,13,14 These results suggest that G- Bcl-2 to promote pro-survival pathways.16,17 ERK has also protein- vsβ-arrestin-dependent signaling promote distinct been shown to phosphorylate and inactivate pro-apoptotic ERK signaling events downstream of the AT1AR. proteins such as caspase 918 and Bim,19 while also enhancing cellular proliferation by activation of proteins involved in Beta-Arrestin-Mediated Activation of nucleic acid synthesis,20 transcription,21,22 and translation.23 The β1AR can activate the EGFR to signal through EGFR Initiates ERK Signaling ERK pathways in aβ-arrestin-dependent manner through a Mitogenic ERK signaling activated by GPCRs has in- process known as “transactivation” (Fig2).9 Transactivation Circulation Journal Vol.72, November 2008 Beta-Arrestin Signaling 1727 Fig3. Theβ-arrestin-mediated
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