Project 463586

Adequate communication between cells is essential for the proper functioning of multicellular organisms. Diffusible signaling molecules and receptors that recognize these molecules at the surface of cells are central components of signaling systems used throughout evolution. G protein-coupled receptors (GPCRs) represent the largest family of proteins involved in such processes and are responsible for the action of a vast diversity of signalling molecules, including hormones, neurotransmitters, chemokines. They also recognize sensory signals such as light, odors and tastants. Given the importance of GPCRs in controlling diverse physiological functions, approximately one third of the prescription drugs used in the clinic work through them by controlling their activity. Classically, GPCR recognize the signals at the cell surface (plasma membrane) where they are accessible to the extracellular milieu. They then transmit the information through the assembly of a signaling machinery at the plasma membrane. However, in recent years, GPCRs were found to engage in non-canonical signaling modalities following their translocation from the cell surface into intracellular vesicles known as endosomes. The mechanisms underlying these newly uncovered signaling modes and their consequences on normal physiology and drug action remain poorly understood. Using a combination of biophysical, pharmacological and cell biology approaches, this project aims at deciphering the molecular and cellular process as well as the functional consequences of the non-canonical signaling engaged by GPCRs in intracellular compartments such as the endosomes. Since different drugs targeting GPCRs have distinctive effects on the subcellular distribution of receptors, in addition to provide new insight on the subcellular regulation of GPCR activity, the present project will allow to explore how drug efficacies could be differentially influenced by endosomal signaling.