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 (AT(1)) 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 AT(1)R-selective antagonists/inverse agonists, in the treatment of heart disease is a testament to the importance of this receptor for cardiovascular homeostasis. Given the pleiotmpic signaling of the cardiovascular AT(1)R 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 AT(1)R ligands that selectively activate beta-arrestin transduction pathways over G(q) protein-dependent pathways. However, by focusing solely on G(q) or beta-arrestins, studies on AT(1)R biased signaling & agonism tend to largely ignore other non-Gq-, non beta-arrestin-dependent signaling modalities the very versatile AT(1)R 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 AT(1)R biased signaling field with a special focus on the non-Gq-, non beta-arrestin-dependent signaling avenues of this receptor in the cardiovascular system, which usually get left out of the conversation of biased AT(1)R signal transduction.

Automated summary

The angiotensin II type 1 receptor, essential in the cardiovascular system, has been extensively studied for its physiological and pathophysiological roles. Biased AT(1) receptor ligands have been developed to selectively activate beta-arrestin transduction pathways. However, the focus on G(q) or beta-arrestins tends to neglect other non-Gq-, non beta-arrestin-dependent signaling modalities employed by the versatile AT(1) receptor in cardiovascular tissues.