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 (AT(1)R) are prescribed to alleviate high blood pressure and its cardiovascular complications. Accordingly, much research has focused on the molecular pharmacology of AT(1)R activation and signaling. An emerging theme is that the AT(1)R generates G protein dependent as well as independent signals and that these transduction systems separately contribute to AT(1)R biology in health and disease. Regulatory molecules termed arrestins are central to this process as is the capacity of AT(1)R to crosstalk with other receptor systems, such as the widely studied transactivation of growth factor receptors. AT(1)R 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 AT(1)R "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 AT(1)R function.

Fig. 1

An expanded RAS. The traditional processing of the precursor, angiotensinogen, by renin and ACE to yield the bioactive peptide AngII is complemented by the generation of alternative angiotensin fragments. These act through an extended family of angiotensin receptors (AT₁R, AT₂R, Mas and IRAP), which may act as monomers and/or as homo-/hetero-dimers, allowing considerable overlap and crosstalk between their respective signal transduction systems. IRAP indicates insulin regulated animo peptidase; inverted triangles indicate protein components with established polymorphisms of altered function that may associate with disease.

Fig. 2

Single nucleotide polymorphisms in the human AT₁R. The 1080 bp coding region of the human AT₁R has 14 putative SNP (see ncbi.nlm.nih.gov/SNP) indicated by arrows. Listed are the nucleotide variations (SNP), their corresponding amino acid position and whether the SNP is silent (synonymous) or results in an alteration in a particular amino acid in the receptor (nonsynonymous change, blue/gray).

Fig. 3

Putative nonsynonymous polymorphisms in the human AT₁R. Shown is the 7 transmembrane-spanning topology of the 359 amino acid human AT₁R; standard single letter coding for the amino acids is used. The N-terminus is extracellular and the carboxyl-terminus is intracellular. Nonsynonymous SNP yielding amino acid changes in the human AT₁R are circled in purple or green, the latter indicating those tested pharmacologically by Hansen et al. (2004a).