Role of βarrestin1 in AT₁R‐mediated mitogen‐activated protein kinase activation in Wistar and SHR brainstem astrocytes

Abstract

barrestin (barr)-1 and -2 are ubiquitously (outside the retina) expressed G-protein-coupled receptor adapter proteins. They uncouple G-protein-coupled receptors from G proteins, internalize the receptor, and subsequently initiate their own wave of signaling independently of G proteins. Angiotensin (Ang) II type 1 receptor (AT 1 R) is a well-established example of a receptor signaling through barrs. Despite the pivotal role of brain AT 1 Rs in the regulation of blood pressure, the involvement of barr-dependent signaling, mediated by AT 1 Rs is not well studied. Particularly, in brain astrocytes very little is known about the effects of barrs in AT 1 R signaling. Herein, we utilized a combination of pharmacological and gene manipulation approaches to investigate the role of barrs in AT 1 R-mediated signaling in isolated brainstem astrocytes from spontaneously hypertensive rats (SHRs) and Wistar rats. We observed that barr1 is the predominant arrestin isoform at the protein level in these cells. Its expression was down-regulated in SHR astrocytes compared to Wistar rat astrocytes. Ang II, contrary to observations in SHR astrocytes where it had no effect, upregulates barr1 protein in Wistar rat astrocytes. We observed differential involvement of barr1 in MAPK activation in brainstem astrocytes of SHR versus Wistar rats. The barr-biased agonist peptide [Sar 1 , Il 4 , Il8] Ang-II (SII), induced AT 1 Rmediated ERK and p38 activation in Wistar rat astrocytes. SII had no effect on ERK and p38 activation in SHRs brainstem astrocytes. Our results indicate, reduced involvement of barr1 in dampening Ang II-induced MAPKs activation and diminished barr1-mediated ERK and p38 activation in SHR brainstem astrocytes. These findings might be mechanistically related to the development of the brain renin-angiotensinaldosterone system hyperactivity, which leads to pathogenesis of the hypertensive state of the SHR model.

Insights Into the Role of Angiotensin-II AT 1 Receptor-Dependent β-Arrestin Signaling in Cardiovascular Disease

“…The mechanisms proposed include reduction in MAPK pathways such as ERK1/2-and p38-phosphorylation. 79 We showed that ICV infusion of TRV027 increased the aversion to saline (ie, decreased saline preference) and lowered blood pressure in the deoxycorticosterone acetate-salt model of hypertension. 81 Further, studies of β-arrestin-1-deficient or β-arrestin-2-deficient mice revealed that deleting β-arrestin-2 stimulates an increase in saline intake and augments the pressor response to deoxycorticosterone acetate-salt hypertension.…”

“…Other studies have also demonstrated that spontaneous hypertensive rat brainstem astrocytes display lower levels of β-arrestin1. 79 Further, overexpression of β-arrestin1 in the rostral ventrolateral medulla (located in the brainstem) of spontaneous hypertensive rats lowered BP with no effect in normotensive controls. 80 Different nuclei in the brainstem are known as key regions for the production, regulation and activation of RAS component.…”

“…The mechanisms proposed include reduction in MAPK pathways such as ERK1/2- and p38-phosphorylation. 79…”

Angiotensin Receptors Heterodimerization and Trafficking: How Much Do They Influence Their Biological Function?

“…β-arrestin signaling induced by AT1R activation in astrocytes might contribute to central control of blood pressure and may be implicated in the pathophysiology of hypertension, given the fact that AT1R signaling through β-arrestins may be involved in the regulation of angiotensinogen production by these cells ( Negussie et al, 2019 ).…”