Unconventional signalling mechanisms mediated by the angiotensin II type 1 receptor in cardiovascular cell types

Angiotensin II (Ang II) is an important effector of the renin-angiotensin system, which plays a critical role in mediating hypertension, cardiac hypertrophy and heart failure. These pathological effects of Ang II on the heart are primarily mediated by the Ang II type 1 (AT1) receptor, a seven transmembrane G protein-coupled receptor. The signalling mechanism of the AT1 receptor is traditionally described as dependent on heterotrimeric G proteins. However, accumulating lines of evidence have suggested that some aspects of AT1 receptor-mediated signalling apparently occur independently of G protein activation. The AT1 receptor also uses a part of its amino acid sequence, the YIPP (tyrosine [Y] isoleucine [I] proline [P] proline [P]) motif, in addition to conventional G protein-dependent mechanisms, to activate tyrosine kinases, such as the epidermal growth factor receptor and Janus kinases (JAK). The AT1 receptor also directly associates with other intracellular molecules, such as AT1 receptor-associated protein. Interaction between the AT1 receptor and these molecules affects the cellular functions of each. Such mechanisms, relying on the specific amino acid sequences of the AT1 receptor, provide the AT1 receptor with a unique modality to communicate with downstream signalling molecules. This review summarises some of these unconventional signalling mechanisms initiated by the AT1 receptor, and their functional significance in cardiovascular diseases. © 2006 Adis Data Information BV. All rights reserved.