What’s new in the renin-angiotensin system?

Abstract.

The type 1 angiotensin receptor (AT₁) activates an array of intracellular signalling pathways that control cell and tissue responses to the peptide hormone angiotensin II (AngII). The capacity of AT₁ receptors to initiate and maintain such signals has typically been explained on the basis of conventional heterotrimeric guanine nucleotide binding protein (G protein) activation, specifically G_q/11. Accumulating evidence from studies utilising a variety of AT₁ receptor mutants and AngII analogues indicates that some important downstream effects of AT₁ receptors are independent of classical G protein coupling. Importantly, AT₁ receptor-mediated endocytosis, tyrosine phosphorylation signalling and mitogen-activated protein kinase activation as well as transactivation of the epidermal growth factor receptor can occur in G_q/11-uncoupled receptor mutants. These observations point to a functional partitioning of AT₁ receptor signals that permits separation of short-term AngII actions (e.g., vasoconstriction) from more extended events, such as pathological cell growth in heart and blood vessels, and may open up new avenues for selective antagonism.