Constitutive activity in the angiotensin II type 1 receptor: discovery and applications.

The pathophysiological actions of the renin-angiotensin system hormone, angiotensin II (AngII), are mainly mediated by the AngII type 1 (AT1) receptor, a GPCR. The intrinsic spontaneous activity of the AT1 receptor in native tissues is difficult to detect due to its low expression levels. However, factors such as the membrane environment, interaction with autoantibodies, and mechanical stretch are known to increase G protein signaling in the absence of AngII. Naturally occurring and disease-causing activating mutations have not been identified in AT1 receptor. Constitutively active mutants (CAMs) of AT1 receptor have been engineered using molecular modeling and site-directed mutagenesis approaches among which substitution of Asn(111) in the transmembrane helix III with glycine or serine results in the highest basal activity of the receptor. Transgenic animal models expressing the CAM AT1 receptors that mimic various in vivo disease conditions have been useful research tools for discovering the pathophysiological role of AT1 receptor and evaluating the therapeutic potential of inverse agonists. This chapter summarizes the studies on the constitutive activity of AT1 receptor in recombinant as well as physiological systems. The impact of the availability of CAM AT1 receptors on our understanding of the molecular mechanisms underlying receptor activation and inverse agonism is described.