Faculty Articles

Title

Biased Agonism/Antagonism at the AngII-AT1 Receptor: Implications for Adrenal Aldosterone Production and Cardiovascular Therapy

ISBN or ISSN

1043-6618

Publication Title

Pharmacological Research

Volume

125

Issue

Part A

Publication Date / Copyright Date

11-2017

First Page

14

Last Page

20

Publisher

Academic Press

DOI Number

10.1016/j.phrs.2017.05.009

Abstract

Many of the effects of angiotensin II (AngII), including adrenocortical aldosterone release, are mediated by the AngII type 1 receptor (AT 1 R), a receptor with essential roles in cardiovascular homeostasis. AT 1 R belongs to the G protein-coupled receptor (GPCR) superfamily, mainly coupling to the G q/11 type of G proteins. However, it also signals through βarrestins, oftentimes in parallel to eliciting G protein-dependent signaling. This has spurred infinite possibilities for cardiovascular pharmacology, since various beneficial effects are purportedly exerted by AT 1 R via βarrestins, unlike AT 1 R-induced G protein-mediated pathways that usually result in damaging cardiovascular effects, including hypertension and aldosterone elevation. Over the past decade however, a number of studies from our group and others have suggested that AT 1 R-induced βarrestin signaling can also be damaging for the heart, similarly to the G protein-dependent one, with regard to aldosterone regulation. Additionally, AT 1 R-induced βarrestin signaling in astrocytes from certain areas of the brain may also play a significant role in central regulation of blood pressure and hypertension pathogenesis. These findings have provided the impetus for testing available angiotensin receptor blockers (ARBs) in their efficacy towards blocking both routes (i.e. both G protein- and βarrestin-dependent) of AT 1 R signaling in vitro and in vivo and also have promoted structure-activity relationship (SAR) studies for the AngII molecule in terms of βarrestin signaling to certain cellular effects, e.g. adrenal aldosterone production. In the present review, we will recount all of these recent studies on adrenal and astrocyte AT 1 R-dependent βarrestin signaling while underlining their implications for cardiovascular pathophysiology and therapy.

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

Keywords

aldosterone, angiotensin receptor antagonists, animals, cardiovascular system, drug agonism, drug antagonism, humans, receptor, angiotensin, type 1

MeSH Subject Heading

adrenal gland, aldosterone angiotensin type 1 receptor, astrocyte heart disease

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