Angiotensin II Type 1 Receptor–Associated Protein Is an Endogenous Inhibitor of Angiotensin II Type 1 Receptor Action in Cardiac Hypertrophy

A ngiotensin II (Ang II) type 1 (AT 1 ) receptor is the primary effector of the renin-angiotensin system and mediates many key physiological and pathological actions of Ang II through a complex orchestration of intracellular signaling molecules. As a G protein-coupled receptor, AT 1 receptor activation induces the canonical G q protein-dependent inositol phosphate turnover and intracellular calcium release pathway, as well as receptor phosphorylation by G protein-coupled receptor kinases and the recruitment of -arrestin as a G proteinindependent pathway to mediate the cellular effects of Ang II. 1 Recent investigations have highlighted the importance of the AT 1 receptor carboxyl-terminal domain that binds to a variety of intracellular proteins, such as G protein-coupled receptor kinases and -arrestin, and plays a pivotal role on receptor internalization, desensitization, phosphorylation, and coupling to G proteins. 1 A relatively new and potentially important player in this orchestra is the AT 1 receptor-associated protein (ATRAP) that interacts with the carboxyl-terminal domain of the AT 1 receptor. ATRAP was first identified and isolated by yeast 2-hybrid screening from the mouse kidney cDNA library in the Dzau laboratory. ATRAP localizes in intracellular trafficking vesicles and plasma membrane, including endoplasmic reticulum, Golgi, and endocytic vesicles. 3 ATRAP interacts selectively with the carboxyl-terminal domain of the AT 1 receptor but not with those of Ang II type 2, m3 muscarinic acetylcholine, bradykinin B2, endothelin B, and 2-adrenergic receptors. 2 ] Tamura's laboratory showed that, in vascular smooth muscle cells in vitro, ATRAP colocalized with the AT 1 receptor, promoted