Cardiovascular angiotensin II type 1 receptor biased signaling: Focus on non-Gq-, non-βarrestin-dependent signaling

Abstract

The physiological and pathophysiological roles of the angiotensin II type 1 (AT₁) receptor, a G protein-coupled receptor ubiquitously expressed throughout the cardiovascular system, have been the focus of intense investigations for decades. The success of angiotensin converting enzyme inhibitors (ACEIs) and of angiotensin receptor blockers (ARBs), which are AT₁R-selective antagonists/inverse agonists, in the treatment of heart disease is a testament to the importance of this receptor for cardiovascular homeostasis. Given the pleiotropic signaling of the cardiovascular AT₁R and, in an effort to develop yet better drugs for heart disease, the concept of biased signaling has been exploited to design and develop biased AT₁R ligands that selectively activate β-arrestin transduction pathways over G_q protein-dependent pathways. However, by focusing solely on G_q or β-arrestins, studies on AT₁R "biased" signaling & agonism tend to largely ignore other non-Gq-, non β-arrestin-dependent signaling modalities the very versatile AT₁R employs in cardiovascular tissues, including two very important types of signal transducers/regulators: other G protein types (e.g., G_i/o, G_12/13) & the Regulator of G protein Signaling (RGS) proteins. In this review, we provide a brief overview of the current state of cardiovascular AT₁R biased signaling field with a special focus on the non-Gq-, non β-arrestin-dependent signaling avenues of this receptor in the cardiovascular system, which usually get left out of the conversation of "biased" AT₁R signal transduction.

Keywords: Angiotensin II type 1 receptor; Angiotensin receptor blocker; Biased signaling; Cardiovascular; G proteins; Regulator of G protein Signaling; β-arrestin.