[Frontiers in Bioscience 14, 958-972, January 1, 2009]

The angiotensin II type 2 (AT2) receptor: an enigmatic seven transmembrane receptor

Enzo R. Porrello1, 2, Lea M.D. Delbridge2, Walter G. Thomas1

1 Molecular Endocrinology Laboratory, Baker Heart Research Institute, Prahran, Victoria 3004, Australia, 2 Department of Physiology, University of Melbourne, Parkville, Victoria 3010, Australia


1. Abstract
2. Introduction
3. AT2 receptor physiology: what does the AT2 receptor do?
3.1. AT2 receptor expression and tissue distribution
3.2. Developmental regulation: AT2 involvement in differentiation and apoptosis
3.3. Vascular responsiveness: AT2 dilator and constrictor actions
3.4. Cardiac fibrosis: AT2 proliferative and anti-proliferative actions
3.5. Myocardial hypertrophy: AT2 pro-growth and anti-growth actions
4. AT2 Receptor signalling: the ongoing search for g protein-coupled signals
4.1. G Protein-coupling
4.2. NO-cGMP
4.3. Activation of phosphatases and dephosphorylation of MAPKs
5. Novel AT2 interacting proteins: screening for new AT2 targets
5.1. ErbB3
5.2. ATIP/ATBP50
5.3. PLZF
6. Signalling without angiotensin II: is the AT2 receptor constitutively active?
7. AT2 receptor dimerization: fact or fantasy?
8. Perspective
9. Acknowledgements
10. References


Angiotensin II (AngII) interacts with two receptor subtypes, AT1 and AT2, belonging to the seven transmembrane receptor superfamily. Pharmacological investigations initially suggested that AT2 receptors antagonize AT1 effects. Data from AT2 receptor transgenic and knock-out mice have not been entirely consistent with this interpretation. At the cellular level, a clear mechanistic model of AT2 transduction and signalling has yet to emerge. The AT2 receptor displays the hallmark motifs and signature residues of a G protein-coupled receptor (GPCR), but fails to demonstrate most of the classic features of GPCR signalling. In recent years, unbiased screens for AT2-interacting proteins have identified novel partner proteins involved in AT2 signalling, providing new insight into the mechanisms of AT2 action. A growing body of evidence suggests that the AT2 receptor is constitutively active (i.e. signals without AngII). This review critically evaluates controversies surrounding physiological functions and signalling mechanisms of the AT2 receptor, primarily in a cardiovascular context. Recent advances in the field are highlighted and findings challenging the concept that the AT2 receptor is a conventional angiotensin receptor are considered.