β-Arrestin–Biased Agonism of the Angiotensin Receptor Induced by Mechanical Stress

Abstract

Abstractβ-Arrestins, which were originally characterized as terminators of heterotrimeric guanine nucleotidebinding protein (G protein)-coupled receptor (GPCR) signaling, also act as important signal transducers. An emerging concept in GPCR signaling is β-arrestin-biased agonism, in which specific ligand-activated GPCR conformational states selectively signal through β-arrestins, rather than through G proteins. Here, we show that mechanical stretch induced β-arrestin-biased signaling downstream of angiotensin II type I receptors (AT1Rs) in the absence of ligand or G protein activation. Mechanical stretch triggered an AT1R-mediated conformational change in β-arrestin similar to that induced by a β-arrestin-biased ligand to selectively stimulate receptor signaling in the absence of detectable G protein activation. Hearts from mice lacking β-arrestin or AT1Rs failed to induce responses to mechanical stretch, as shown by blunted extra-cellular signal-regulated kinase and Akt activation, impaired transactivation of the epidermal growth factor receptor, and enhanced myocyte apoptosis. These data show that the heart responds to acute increases in mechanical stress by activating β-arrestin-mediated cell survival signals.

Long Range Effect of Mutations on Specific Conformational Changes in the Extracellular Loop 2 of Angiotensin II Type 1 Receptor

“…The mutation-induced conformational changes were analyzed by RCAM analysis of four Cys reporters introduced in ECL2. In our previous study RCAM was shown to depict specific conformational changes in ECL2 upon binding of the ligand in the orthosteric site of cell surface AT1R in the intact cells under conditions used for signal transduction studies (27)(28)(29)(30)(31). The RCAM analysis in this study indicated the presence of a distinct ECL2 lid conformation in the empty state of the gain of function AT1R mutant but not in the loss of function receptor mutant.…”

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…In cardiac cells, EGFR transactivation has been linked to angiotensin (Rakesh et al, 2010), muscarinic (Krieg et al, 2002;Krieg et al, 2004;Miao et al, 2015), endothelin (Kodama et al, 2002;Chen et al, 2006), opioid (Cao et al, 2005;Cohen et al, 2007;Forster et al, 2007;Zhang et al, 2015), bradykinin (Methner et al, 2009), adrenergic (Noma et al, 2007;Grisanti et al, 2014), adenosine (Williams-Pritchard et al, 2011), and sphoingosine-1 phosphate (S1P) (Hofmann et al, 2009) GPCRs, with transactivation via angiotensin II (Ang II) perhaps the most well studied. Several Gq-linked receptors (Ang II, ET-1, -ARs) may promote cardiac hypertrophy/remodelling, whereas transactivation by adenosine, opioid, bradykinin or muscarinic receptors may be protective, enhancing cell survival.…”

“…Cardiac protection and survival kinase activation in response to adenosine receptor agonism (and ischaemic preconditioning) is also associated with EGFR phosphorylation and blocked by EGFR, MMP or HB-EGF inhibitors (Williams-Pritchard et al, 2011). Finally, mechanical stress has been shown to trigger β-arrestin-dependent AT1 receptor activation, leading to EGFR transactivation and protection of cardiac myocytes from apoptosis (Rakesh et al, 2010).…”

“…Several studies highlight G protein independent/arrestin dependent signalling in cardioprotective EGFR transactivation (Noma et al, 2007). Mechanical stretch has also been shown to trigger an AT1 receptor-mediated conformational change in -arrestin to selectively stimulate receptor signalling in the absence of G protein activation (Rakesh et al, 2010). In contrast, protective -opioid receptor activation of kinase signalling appears to involve PKCdependent control of ligand shedding, and -arrestin2 recruitment downstream of the EGFR (Zhang et al, 2015).…”

GPCRs and cancer

“…As it concerns β-arrestins, they can also function as molecular mediators of G protein-independent signaling by activating a variety of transduction proteins like Src family kinases and components of the MAPK cascades [166,168,169] . On the basis of these findings, β-arrestins were included among the signaling factors mediating the action of diverse GPCRs in cancer [170] .…”