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Since its discovery, more than twenty-five years ago, the angiotensin AT2 receptor (AT2R) has puzzled the scientific community because of its distinct localization, regulation, signalling pathway and biological effects separating it clearly from the classical features of the renin-angiotensin system (RAS) mediated by the angiotensin AT1 receptor. Intensive research over the years has revealed major characteristics of the AT2R as a modulatory player involved in anti-proliferation, anti-inflammation, natriuresis, neuroregeneration and apoptosis, i.e. biological programs that can counterbalance patholological processes and enable recovery from disease. The AT2R has thus mutated from an ?enigmatic? receptor to a significant member of the ?protective arm? of the RAS. The recent development of novel, small moleculeand peptide-derived AT2R agonists offers a therapeutic potential in humans with a variety of clinical indications. The ?enigmatic receptor? is a designation of the angiotensin AT2 receptor (AT2R) from the very beginning of its discovery more than 25 years ago in the late 1980s. ?Enigmatic? because of constitutive action, atypical intracellular signalling and ?hidden? (patho)physiological functions that took years, almost decades, to unveil. Even today the various actions, some of them stil l controversial, the numerous intracellular signalling pathways, the interaction with other membrane receptors and the role of the AT2R in the context of the renin-angiotensin system (RAS), are far from being fully elucidated. We at least know much more than in the early days about the AT2R, we can confidently classify it as an important member of the ?protective arm ? of the RAS (Figure 1) and we have even identif ied this receptor as a therapeutic target. Figure 1 The Renin-Angiotensin System with its ?classical? arms (in red) and its ?protective arms? (in green) Continued overleaf DOI: 10.30824/1803-8

The Angiotensin AT2 Receptor: A major constituent of the "Protective Arm" of the Renin-Angiotensin System