Angiotensin II Receptor–Induced Cardiac Remodeling in Mice Without Angiotensin II

Abstract

See related article, pp 627–633 Cell surface receptors and their ligands cooperatively regulate physiological processes. The receptor activity is regulated positively when agonists bind and negatively when antagonists displace the agonists. Complete absence of a hormone should abrogate physiological and pathogenic functions regulated by the cognate receptor. However, awareness of the constitutive activity, the ability of native receptors to become functionally active in absence of hormone, is changing our view of the robustness of ligand-regulated receptor mechanisms. Paradigms of constitutive activity of G protein–coupled receptors (GPCRs) and inverse agonist activity of GPCR-targeted drugs are firmly established. The GPCR, angiotensin II (Ang II) type 1 receptor (AT1R), can be spontaneously active.1 Ways such as membrane environment, interacting proteins, receptor autoantibodies, and single nucleotide polymorphisms that increase expression can increase G-protein signaling in the absence of Ang II using the potential energy of the receptor.2 Inverse agonists can suppress the constitutive activity of a receptor; however, classic antagonists cannot perform this action1,2 (Figure). Figure. Mechanism of the constitutively active angiotensin II type 1 receptor (AT1R) signaling is shown in blue. The classic agonist-activated AT1R signaling is shown in black and white. GRK indicates G protein–coupled receptor kinase; P, phosphorylation. Constitutive activity is an inherent property of a GPCR in all, including human and animal, species.1–3 Wild-type AT1R stimulates significant G protein signaling in the absence of Ang II, when 1 to 10 pmol/mg of receptor is expressed in cell lines. The constitutively active pool of wild-type AT1R is <5%, which is the reason why it is difficult to detect it with the …