Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

Abstract

AT angiotensin receptor (ATR), a prototypical G protein-coupled receptor (GPCR), is the main receptor, which mediates the effects of the renin-angiotensin system (RAS). ATR plays a crucial role in the regulation of blood pressure and salt-water homeostasis, and in the development of pathological conditions, such as hypertension, heart failure, cardiovascular remodeling, renal fibrosis, inflammation, and metabolic disorders. Stimulation of ATR leads to pleiotropic signal transduction pathways generating arrays of complex cellular responses. Growing amount of evidence shows that ATR is a versatile GPCR, which has multiple unique faces with distinct conformations and signaling properties providing new opportunities for functionally selective pharmacological targeting of the receptor. Biased ligands of ATR have been developed to selectively activate the β-arrestin pathway, which may have therapeutic benefits compared to the conventional angiotensin converting enzyme inhibitors and angiotensin receptor blockers. In this review, we provide a summary about the most recent findings and novel aspects of the ATR function, signaling, regulation, dimerization or oligomerization and its cross-talk with other receptors, including epidermal growth factor (EGF) receptor, adrenergic receptors and CB cannabinoid receptor. Better understanding of the mechanisms and structural aspects of ATR activation and cross-talk can lead to the development of novel type of drugs for the treatment of cardiovascular and other diseases.

Interplay Between Angiotensin II Type 1 Receptor and Thrombin Receptor Revealed by Bioluminescence Resonance Energy Transfer Assay

“…Thus, our data reveal for the first time the possible interplay between AT1R and PAR1 when coexpressed in HEK293 cells. This comes to extend the list of GPCR members potentially interacting or interplaying with AT1R (Takezako et al, 2017;Toth et al, 2018) or PAR1 (Arachiche et al, 2013;Lin and Trejo, 2013) reported in many contexts and models.…”

Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

“…In addition to dual drug therapy, the ability of the CB1R to dimerize with other receptors can also be leveraged to design novel therapies. The CB1R has a high tendency to crosstalk with several different GPCRs, including but not limited to the AT1R and the opioid receptors [ 141 , 145 , 602 , 603 , 604 ]. Since receptor heteromers are selectively expressed in only distinct pathological conditions [ 605 , 606 ], targeting heteromeric complexes has been discussed as a viable therapeutic strategy [ 607 ].…”

Effect of novel GPCR ligands on blood pressure and vascular homeostasis

“…Gq protein signaling can also regulate Rho-GEFs leading to the activation of the Rac or Rho/ROCK signaling pathways. AT1R coupled to Gi/o inhibits adenylyl cyclase and some Ca++ channels and activates Rho kinase (Toth, Turu, Hunyady, & Balla, 2018). The Gβ2 subunit of the G protein interacted with specific nucleosome core histones and sequence motif of several transcription factors (Bhatnagar et al, 2013).…”

“…β-Arrestins also serve as docking platforms for ERKs leading to a different mode of MAPK signaling cascade involved mainly in cell proliferation and survival (Kim, Ahn, Rajagopal, & Lefkowitz, 2009). These events are called second wave AT1R signaling (Toth et al, 2018). The G protein-dependent and -independent signaling waves of AT1R occur in different time and space in a cell.…”