The textured cellular signaling and endocytic profile of the cardioprotective Angiotensin-(1-7) peptide.

• Applicant: Professorin Dr. Evi Kostenis
• Subject Area: Pharmacology ; Pharmacy
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562664783

Hormone receptor systems play a crucial role in maintaining the homeostasis of living organisms. Two members of the hormone family are the peptides angiotensin II (Ang II) and angiotensin(1-7) (Ang(1-7)). Both hormonal peptides exert their biological effects via plasma membrane angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors, members of the G protein-coupled receptor (GPCR) family. Ang II activation of the AT1R is largely responsible for the regulation of blood pressure and volume, and increased activation of the AT1R by Ang II is associated with the development of cardiovascular disease. Ang(1-7) is generated from Ang II by proteolytic cleavage of a C-terminal amino acid, but its biological profile is completely distinct. In contrast to Ang II, Ang(1-7) is associated with a number of beneficial cardiovascular effects, the molecular basis of which remains controversial and enigmatic. The aim of this proposal is to elucidate these molecular details, more specifically the molecular mechanisms underlying the cellular actions of Ang(1-7). Some of the biological effects of Ang(1-7) can be attributed to direct competition with Ang II for the AT1R, thereby preventing full receptor activation. However, Ang(1-7) also exerts other effects that are likely to result from its own signalling. Earlier studies have proposed that G-protein-independent, arrestin-dependent signalling is the fundamental mechanism underlying the cellular signalling (and beneficial cardioprotective profile) of Ang(1-7). This conclusion is at odds with more recent findings from our own research and that of others, suggesting that the purported arrestin-dependent signalling is in fact G-protein dependent. In this project, we aim to resolve this debate by elucidating the principles of signalling and trafficking employed by Ang(1-7) to propagate its cellular effects through the AT1R using a combination of existing and newly developed methodologies with genetic and pharmacological manipulations. The majority of experiments will be performed in HEK293 cells exogenously expressing the AT1R, because this cellular background has been used to coin the paradigmatic mode of G protein-independent, arrestin-biased signaling. Elucidation of these molecular principles is fundamental to the development of ligands that mimic the behaviour of an endogenous hormone for use in in vivo models and in patients, and ultimately for therapeutic benefit.

• DFG Programme: Research Grants