TY - JOUR T1 - The Angiotensin AT<sub>2</sub> Receptor: From a Binding Site to a Novel Therapeutic Target JF - Pharmacological Reviews JO - Pharmacol Rev SP - 1051 LP - 1135 DO - 10.1124/pharmrev.120.000281 VL - 74 IS - 4 AU - U. Muscha Steckelings AU - Robert E. Widdop AU - Edward D. Sturrock AU - Lizelle Lubbe AU - Tahir Hussain AU - Elena Kaschina AU - Thomas Unger AU - Anders Hallberg AU - Robert M. Carey AU - Colin Sumners A2 - Touyz, Rhian Y1 - 2022/10/01 UR - http://pharmrev.aspetjournals.org/content/74/4/1051.abstract N2 - Discovered more than 30 years ago, the angiotensin AT2 receptor (AT2R) has evolved from a binding site with unknown function to a firmly established major effector within the protective arm of the renin-angiotensin system (RAS) and a target for new drugs in development. The AT2R represents an endogenous protective mechanism that can be manipulated in the majority of preclinical models to alleviate lung, renal, cardiovascular, metabolic, cutaneous, and neural diseases as well as cancer. This article is a comprehensive review summarizing our current knowledge of the AT2R, from its discovery to its position within the RAS and its overall functions. This is followed by an in-depth look at the characteristics of the AT2R, including its structure, intracellular signaling, homo- and heterodimerization, and expression. AT2R-selective ligands, from endogenous peptides to synthetic peptides and nonpeptide molecules that are used as research tools, are discussed. Finally, we summarize the known physiological roles of the AT2R and its abundant protective effects in multiple experimental disease models and expound on AT2R ligands that are undergoing development for clinical use. The present review highlights the controversial aspects and gaps in our knowledge of this receptor and illuminates future perspectives for AT2R research.Significance Statement The angiotensin AT2 receptor (AT2R) is now regarded as a fully functional and important component of the renin-angiotensin system, with the potential of exerting protective actions in a variety of diseases. This review provides an in-depth view of the AT2R, which has progressed from being an enigma to becoming a therapeutic target. ER -