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

Abstract

Angiotensin II (Ang II) type 1 (AT1) 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, AT1 receptor activation induces the canonical Gq 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 β-arrestin as a G protein–independent pathway to mediate the cellular effects of Ang II.1 Recent investigations have highlighted the importance of the AT1 receptor carboxyl-terminal domain that binds to a variety of intracellular proteins, such as G protein–coupled receptor kinases and β-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 AT1 receptor–associated protein (ATRAP) that interacts with the carboxyl-terminal domain of the AT1 receptor. ATRAP was first identified and isolated by yeast 2-hybrid screening from the mouse kidney cDNA library in the Dzau laboratory.2 ATRAP is a relatively small 18-kDa protein with 1 potential N-glycosylation site, 1 potential phosphorylation site for protein kinase C, 1 potential phosphorylation site for casein kinase II, and 3 hydrophobic domains for potential transmembrane binding.2,3 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 AT1 receptor but not with those of Ang II type 2, m3 muscarinic acetylcholine, bradykinin B2, …