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Angiotensin II type 1 receptor signaling – Functional selectivity and receptor cross-talk

Jonas Tind Hansen

Summary

The focus of this PhD thesis is to investigate the different aspects of Angiotensin II (AngII) type 1 receptor (AT1R) activation and signaling. The AT1R belongs to the largest family of signaling proteins called seven transmembrane (7TM) receptors, also known as G protein coupled receptors (GPCRs). The AT1R is a key regulator of cardiovascular physiology maintaining regulation of blood pressure and water-salt balance, and is an important drug target in cardiovascular disease. The mechanism of 7TM receptor signaling is categorized as binding of an agonist to the receptor that promotes a conformational change, which results in the activation of receptor-associated heterotrimeric G proteins and consequent downstream signaling. Following this, the receptor is phosphorylated by various kinases and recruits β-arrestins, which terminate G protein signaling by receptor desensitization and consequently internalization. In addition, 7TM receptors can signal independent of G proteins mediated by β-arrestin by interacting with signaling molecules and promote intracellular signaling. 

The different aspects of AT1R activation and signaling include cross-talk between AT1R and other 7TM receptors, and functional selectivity of AT1R signaling. Cross-talk can be defined as a functional interaction between two (or more) signaling pathways. In one paper, we show that some of the early studies on cross-talk involving the AT1R are not a function of heterodimerization, as earlier proclaimed (paper 1). However, many studies reveals cross-talk between distinct receptors, and we show by an extensive investigation of 7TM receptors’ influence on AT1R signaling, that the Thromboxane A2α receptor uniquely enhanced AngII-stimulated response of the AT1R (paper 4). Functional selectively is categorized by a ligands ability to differential activate G protein-dependent and/or β-arrestin-mediated signaling. We investigated the AT1R’s ability to signaling through different pathways, by applying mutations in the AT1R known to be important for receptor signaling including G protein-dependent and G protein-independent signaling (paper 3). In another paper, we determined the interaction between the AT1R and β-arrestin1 and 2, respectively, to elucidate the pharmacology of different ligands (paper 2). These results suggest that the AT1R can exhibit distinct conformations upon specific ligand binding to the receptor. 

The presented results clearly demonstrate that AT1R activation and signaling is very complex, and a broad range of parameters has to be included to completely elucidate AT1R receptor signaling.