RT Journal Article SR Electronic T1 The Angiotensin AT2 Receptor: From a Binding Site to a Novel Therapeutic Target JF Pharmacological Reviews JO Pharmacol Rev FD American Society for Pharmacology and Experimental Therapeutics SP 1051 OP 1135 DO 10.1124/pharmrev.120.000281 VO 74 IS 4 A1 Steckelings, U. Muscha A1 Widdop, Robert E. A1 Sturrock, Edward D. A1 Lubbe, Lizelle A1 Hussain, Tahir A1 Kaschina, Elena A1 Unger, Thomas A1 Hallberg, Anders A1 Carey, Robert M. A1 Sumners, Colin A2 Touyz, Rhian YR 2022 UL http://pharmrev.aspetjournals.org/content/74/4/1051.abstract AB 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.