Mechanisms and functions of agonist-independent activation in the angiotensin II type 1 receptor

The angiotensin II (AngII) type 1 (AT1) receptor is a seven-transmembrane G protein-coupled receptor, and is involved in regulating the physiological and pathological process of the cardiovascular system. Systemically and locally generated AngII has agonistic action on AT1 receptor, but recent studies have demonstrated that AT1 receptor inherently shows spontaneous activity even in the absence of AngII. Furthermore, mechanical stress can activate AT1 receptor by inducing conformational switch without the involvement of AngII, and induce cardiac hypertrophy in vivo. These agonist-independent activities of AT1 receptor can be inhibited by inverse agonists, but not by neutral antagonists. Considerable attention has been directed to molecular mechanisms and clinical implications of agonist-independent AT1 receptor activation, and inverse agonist activity emerges as an important pharmacological parameter for AT1 receptor blockers that will improve efficacy and expand therapeutic potentials in cardiovascular medicine.