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Molecular determinants of Angiotensin II type 1 receptor activation


Marie Mi Bonde Hansen


The primary focus of this thesis has been to investigate different aspects of molecular mechanismsunderlying Angiotensin II Type 1 receptor (AT1R) activation. The AT1R belongs to the large proteinsuperfamily of seven transmembrane receptors (7TMRs), is central in blood pressure homeostasis, and isinvolved in the pathology of cardiovascular disease. The activation mechanism of 7TMRs remains to becompletely resolved, but most likely comprises of concerted conformational changes within the helicalbundle. In recent years, it has become evident that 7TMR signalling is far more extensive than signalingthrough G proteins, but also involves G protein‐independent pathways, which ultimately could allow forpharmacological separation of physiological outcome. We have studied general AT1R activation through apatch of amino acids important for maintenance of the inactive state identified using bioinformatical tools.In a second study, we focused on the molecular determinants of the ability of the receptor to selectivelyactivate G protein‐independent signaling pathways. Here, we perturbed the ability of the receptor tointeract with β‐arrestins for AT1R mutants previously found to be differentially activated. Together, thesestudies have shown that the mechanisms of activation, full and differential, are complex and thoughmolecular features may be shared between at least Family A 7TMRs, factors such as the ability to activate Gprotein‐independent pathways including the nature of interaction with beta arrestin are important to takeinto account when interpreting signalling endpoints. In an additional study, the ability of AT1R antagoniststo bind and activate the closely related bradykinin B2 receptor was investigated. We found that theantagonist Losartan acted as a partial agonist, while none of the other compounds had any effect. Based onthese results, we hypothesize that this ability of Losartan may be involved in some of the cardioprotectiveeffects of the compound.