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

Abstract

Abstractβarrestin (βarr)‐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 (AT1R) is a well‐established example of a receptor signaling through βarrs. Despite the pivotal role of brain AT1Rs in the regulation of blood pressure, the involvement of βarr‐dependent signaling, mediated by AT1Rs is not well studied. Particularly, in brain astrocytes very little is known about the effects of βarrs in AT1R signaling. Herein, we utilized a combination of pharmacological and gene manipulation approaches to investigate the role of βarrs in AT1R‐mediated signaling in isolated brainstem astrocytes from spontaneously hypertensive rats (SHRs) and Wistar rats. We observed that βarr1 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, up‐regulates βarr1 protein in Wistar rat astrocytes. We observed differential involvement of βarr1 in MAPK activation in brainstem astrocytes of SHR versus Wistar rats. The βarr‐biased agonist peptide [Sar1, Il4, Il8] Ang‐II (SII), induced AT1R‐mediated 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 βarr1 in dampening Ang II‐induced MAPKs activation and diminished βarr1‐mediated ERK and p38 activation in SHR brainstem astrocytes. These findings might be mechanistically related to the development of the brain renin–angiotensin–aldosterone system hyperactivity, which leads to pathogenesis of the hypertensive state of the SHR model. image