Section: New Results

Analysis of FSH and Angiotensine Signaling

Participants : François Fages, Domitille Heitzler, Aurélien Rizk, Sylvain Soliman.

In [6] in collaboration with Eric Reiter (UMR CNRS-INRA 6175) and Frédérique Clément (SISYPHE) in the framework of the Initiative Action REGATE , we have combined experimental approaches with computational modeling to decipher the molecular mechanisms as well as the hidden dynamics governing ERK activation by the angiotensin II type 1A receptor (AT1AR) in HEK293 cells. We have built in BIOCHAM a dynamical model that captures available knowledge and experimental data. The unknown kinetic parameters have been inferred using a temporal logic specification of experimental data in both control and perturbed conditions, using a cluster of 10000 processors at the GENCI.

The mathematical model predicts and experiments confirm that, for the AT1AR expressed in HEK293 cells: i) GRK2/3 and 5/6 regulate switching between the G protein and β-arrestin pathways as well as their distinct dynamics by phosphorylating the C- terminal region of the activated receptor; ii) GRK2/3 not only mediates desensitization of G protein activation but also exerts a strong restraining influence on β-arrestin signaling; iii) GRK5/6 exert little effect on G protein-stimulated ERK but are required for β-arrestin- mediated ERK activation; iv) the β-arrestin-dependent ERK pathway undergoes both activation and deactivation through amplified enzymatic processes.

These results convincingly illustrate the value of using computational modeling to decipher the complex signaling mechanisms elicited by 7TMRs [1] . This approach is applied more generally to G protein-coupled receptor signaling which is of great importance in pharmacology.