Type 1 angiotensin receptor pharmacology: Signaling beyond G proteins

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.