Type 1 angiotensin receptor pharmacology: Signaling beyond G proteins

Abstract

Drugs that inhibit the production of angiotensin II (AngII) or its access to the type 1 angiotensin receptor (AT₁R) are prescribed to alleviate high blood pressure and its cardiovascular complications. Accordingly, much research has focused on the molecular pharmacology of AT₁R activation and signaling. An emerging theme is that the AT₁R generates G protein dependent as well as independent signals and that these transduction systems separately contribute to AT₁R biology in health and disease. Regulatory molecules termed arrestins are central to this process as is the capacity of AT₁R to crosstalk with other receptor systems, such as the widely studied transactivation of growth factor receptors. AT₁R function can also be modulated by polymorphisms in the AGTR gene, which may significantly alter receptor expression and function; a capacity of the receptor to dimerize/oligomerize with altered pharmacology; and by the cellular environment in which the receptor resides. Together, these aspects of the AT₁R “flavour” the response to angiotensin; they may also contribute to disease, determine the efficacy of current drugs and offer a unique opportunity to develop new therapeutics that antagonize only selective facets of AT₁R function.