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

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 Gq protein-dependent pathways. However, by focusing solely on Gq 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., Gi/o, G12/13) & 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. [Display omitted]