Mechanoactivation of the angiotensin II type 1 receptor induces β‐arrestin‐biased signaling through Gα_i coupling

Abstract

Ligand activation of the angiotensin II type 1 receptor (AT1R), a member of the G protein-coupled receptor (GPCR) family, stimulates intracellular signaling to mediate a variety of physiological responses. The AT1R is also known to be a mechanical sensor. When activated by mechanical stretch, the AT1R can signal via the multifunctional adaptor protein β-arrestin, rather than through classical heterotrimeric G protein pathways. To date, the AT1R conformation induced by membrane stretch in the absence of ligand was thought to be the same as that induced by β-arrestin-biased agonists, which selectively engage β-arrestin thereby preventing G protein coupling. Here, we show that in contrast to the β-arrestin-biased agonists TRV120023 and TRV120026, membrane stretch uniquely promotes the coupling of the inhibitory G protein (Gαi) to the AT1R to transduce signaling. Stretch-triggered AT1R-Gαi coupling is required for the recruitment of β-arrestin2 and activation of downstream signaling pathways, such as EGFR transactivation and ERK phosphorylation. Our findings demonstrate additional complexity in the mechanism of receptor bias in which the recruitment of Gαi is required for allosteric mechanoactivation of the AT1R-induced β-arrestin-biased signaling.

Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

“…There is a growing number of evidence that AT 1 R not only behaves as a hormone receptor, but also serves as a sensor of membrane stretch [52][53][54][55]. In that function, AT 1 R is activated in the absence of ligand binding and shows biased signaling properties.…”

“…In that function, AT 1 R is activated in the absence of ligand binding and shows biased signaling properties. Upon osmotic stretch, AT 1 R binds β-arrestin in a G i/o activity dependent manner, but does not activate G q/11 proteins [55]. These processes are followed by the transactivation of epidermal growth factor receptor (EGFR) and activation of ERK [55].…”

“…Upon osmotic stretch, AT 1 R binds β-arrestin in a G i/o activity dependent manner, but does not activate G q/11 proteins [55]. These processes are followed by the transactivation of epidermal growth factor receptor (EGFR) and activation of ERK [55]. This mechanism was suggested to mediate the Frank-Starling law of the heart, i.e.…”

Molecular interactions betweenNeisseria meningitidisand its human host

“…Interestingly, some GPCRs were described as mechanosensors and, as such, may sense membrane tension. For instance, angiotensin II type 1 receptor is capable of sensing membrane stretching (Wang, Hanada, Gareri, & Rockman, 2018) and parathyroid hormone type 1 receptor senses mechanochemical signals in preosteoblatic cells (Zhang, Frangos, & Chachisvilis, 2009). The possibility that CD147 and/or the β2AR can be involved in mechanosensing of Tfp pulling forces needs to be further studied.…”

Label-free cell signaling pathway deconvolution of angiotensin type 1 receptor reveals time-resolved G-protein activity and distinct AngII and AngIIIIV responses

“…Despite all these evidences for It was previously shown in rat adrenal glomeruli, liver, kidney, and pituitary cells that AT1R couples to Gi/o proteins, thus inhibiting adenylyl cyclase activity [3,50]. Gi is also the only signaling pathway activated by AT1R after ligand-independent mechanoactivation [51]. Our results with HEK293-AT1R cells treated with PTX, a Gi/o inhibitor [52], revealed a contribution of these G proteins in the phase II of the cellular response measured by SPR ( Table 1) that could be due to a modulation of ERK1/2 activity [3,52].…”