Regulatory Peptides 81 (1999) 11–24 Invited review The AT receptor: fact, fancy and fantasy 2 a,b, a,b * M. de Gasparo , H.M. Siragy a Novartis Pharma AG, Basel, Switzerland b Department of Medicine, University of Virginia, Charlottesville, VA, USA Received 25 January 1999 Abstract The angiotensin AT receptor subtype was recently cloned and pharmacologically characterized but its function still remains elusive 2 and controversial. It is a member of the G-protein coupled receptor superfamily with a minimal sequence homology with the AT 1 receptor, responsible for the known effect of angiotensin II. The AT receptor displays a totally different signaling mechanisms from the 2 AT receptor and involves various phosphatases. It is expressed at low density in adult tissues but up-regulated in pathological 1 circumstances. Clearly, the AT receptor has antiproliferative properties and therefore opposes the growth promoting effect linked to the 2 AT receptor stimulation. It is also reported that the AT receptor regulates ionic fluxes, affects differentiation and nerve regeneration, has 1 2 anti-angiogenic and anti-fibrotic properties and stimulates apoptosis. However, the results, although suggestive, are sometimes equivocal. Obviously, the AT receptor plays a role in the pathogenesis and remodeling of cardiovascular and renal diseases. A more extensive 2 knowledge of the AT receptor could therefore contribute to the understanding of the clincial beneficial effects of the AT receptor 2 1 antagonists.  1999 Elsevier Science B.V. All rights reserved. Keywords: Angiotensin; Angiotensin receptor antagonist; Apoptosis; Brain; Collagen; Fibrosis; Heart; Kidney; Proliferation; Reproduc- tion; Signaling; Vessel 1. Introduction 2. Structure and coupling mechanism Although the biological effects of the renin-angiotensin The AT receptor is a member of the superfamily of 2 system (RAS) have been the focus of many studies for G-protein coupled receptors that have seven-transmem- several years, the functions of some of its individual brane regions. The cDNA for this receptor encodes a 363 components still remain poorly defined. The angiotensin II amino-acid protein (Fig. 1) with a molecular weight of subtype-2 (AT ) receptor was identified several years ago, 41 220 Da and shares only about 34% sequence homology 2 however, its role in physiology and pathophysiology with the angiotensin subtype-1 (AT ) receptor [1,2]. AT 1 2 remains elusive and is not well understood. The AT receptor protein contains five potential N-glycosylation 2 receptor was initially identified and characterized in phar- sites in the extracellular N-terminus and 14 cysteine 101 167 199 macological studies using native receptor from tissues and residues. Lys , Arg and Lys , which are considered cell lines. Later, it was cloned and sequenced. In this to be essential for Ang II binding to the AT receptor, are 1 review, we critically discuss some aspects of our current conserved in the AT receptor. As for other G-protein 2 141 knowledge of the AT receptor. coupled receptors, the highly conserved sequence Asp - 2 142 143 Arg -Tyr in the second cytosolic loop is crucial for 122 binding to the AT receptor. Mutation of Arg and 2 *Corresponding author. Tel.: 1 41-61-696-37-47; fax: 1 41-61-696- 297 108 Asp but not Tyr significantly impaired Ang II 26-51. binding [3]. Also, there is a potential protein kinase-C E-mail address: marc.de gasparo@pharma.novartis.com (M. de ] Gasparo) phosphorylation site in the second intracellular loop and 0167-0115 / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0167-0115(99)00023-3