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After activation by their ligands, GPCRs are desensitized and internalized in intracellular compartments. It has recently been established that GPCRs induce signaling pathways from intracellular compartments, a process that plays a critical role in an increasing number of physiological functions. In this context, BIOS initiated a new axis of research, initially focusing on LHR and FSHR receptors. Indeed, observations published by the team have shown that for these receptors, the production of the second messenger (cAMP) occurs first at the plasma membrane, then from the endosomes following internalization of the receptor.

The main question of this axis is to demonstrate the importance of the spatio-temporal dimension of FSHR and LHR signaling on male and female reproduction. To do this, the team seeks to highlight biased ligands (see #Signaling bias) favoring signaling from the plasma membrane and/or different cellular compartments. With the joint Musca project team and collaborators, we are implementing suitable mathematical tools (biochemical reaction networks, coagulation-fragmentation processes) to model and calibrate spatio-temporal models of compartmentalization of cell signaling.
At the experimental level, fluorescent sensors suitable for real-time imaging in different compartments and targeted proteomics approaches to characterize endosomal compartments are currently being tested to monitor and control in real time the signaling from the different cellular compartments at the level of a single cell.

Fundings:

1. ANR MOSDER, Frédéric Jean-Alphonse (2022-2026), 1 academic partner, leader
2. Métaprogramme DIGIT-BIO IMAGO, Frédéric Jean-Alphonse (2022-2024), 4 academic partners, leader
3. Appel Exploratoire INRIA, Romain Yvinec (2022-2024), 1 academic partner, leader. See Inria web page.
4. LabEx MabImprove.

Team people involved:

Ph.D. student : Juliette Gourdon
Postdocs : Léo Darrigade
Researchers : Frédéric Jean-Alphonse, Eric Reiter, Yves Combarnous, Danièle Klett, Romain Yvinec

Communautés scientifiques: GDR Reproscience, IRN GPCRnet, LabEx MAbImprove, RT MathSAV, EPC Musca