Trends in Endocrinology & Metabolism
ReviewSignal Transduction from the Angiotensin II AT2 Receptor
Section snippets
Physiological Functions Attributed to the AT2 Receptor
Studies performed in vivo by administration of AT2-selective ligands in conjunction with recently developed transgenic animal models have established active roles for the AT2 receptor in cardiovascular and renal functions, in central nervous system actions and in developmental processes. One important emerging function of the AT2 receptor also concerns attenuation of the physiological effects mediated by the AT1 subtype.
Disruption of the gene encoding AT2 (Agtr2) in mice has outlined a negative
Signaling Pathways Activated by the AT2 Receptor
Although structurally related to G- protein-coupled receptors, the AT2 receptor displays atypical signal transduction and G-protein-coupling mechanisms1. While early studies led to disparate and mostly controversial results, it is now becoming clear that AT2 activates three major cascades of intracellular events: (1) activation of protein phosphatases and protein dephosphorylation; (2) regulation of the nitric oxide (NO)–cGMP system; and (3) stimulation of phospholipase A2 (PLA2) and release of
AT2 Receptor Coupling to Protein Phosphatases
Coupling to tyrosine phosphatases is the first and most original signaling pathway associated with AT2 receptor activation. Despite very few early studies reporting AT2-induced phosphatase inhibition, a general consensus now exists in the literature in favor of AT2-mediated activation of phosphatases in several cell types and cellular responses20, 21, 22, 23, 25, 27, 28.
To date, three AT2-associated phosphatases (SHP-1, PP2A and MKP-1) have been identified. All three enzymes contribute to AT2
Negative Crosstalk between AT1 and AT2 Receptor Subtypes
In numerous studies, including knockout experiments, the AT2 receptor has been shown to counteract the effects of Ang II mediated by the AT1 receptor, suggesting that AT2 might provide a brake for the hormonal signal. Accordingly, several studies have found opposite intracellular effects of the AT1 and AT2 receptors, particularly on the regulation of protein kinases and phosphorylation24, 26, 38. Because Ang II binds to its two receptor subtypes AT1 and AT2 with a similar affinity, the cellular
Acknowledgements
This work was supported by the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, University Paris VII, the Association pour la Recherche sur le Cancer, the Ligue Nationale contre le Cancer, the Fondation pour la Recherche Medicale and the Ligue Contre le Cancer Comité de Paris.
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