Addressing functional selectivity in GPCR signaling: the ghrelin receptor – GHS-R SIG

G protein-coupled receptors (GPCR) represent the single largest family of cell surface receptors involved in signal transduction. They therefore represent major targets for the development of drug candidates with potential application in all clinical fields. In fact, more than 50% of the drugs prescribed today act by activating or blocking a GPCR. However, our ability to fully exploit the therapeutic potential of these receptors is still limited by our incomplete understanding of how GPCR signaling efficacy and selectivity are regulated. Basic research recently highlighted very important new concepts that open new exciting possibilities for drug design. These include the concept of ligand-biased efficacy that relies on the observation that some molecules possess dual and opposite efficacies toward different pathways as well as the observation that GPCRs can form multimeric complexes with specific functional and pharmacological properties. With the intent of addressing the molecular bases of functional selectivity in GPCR signaling, we assembled here a team of scientists with established expertise in the field of GPCR structure/function analyses, pharmacology and chemistry. This will allow us to develop a unique multidisciplinary strategy associating theoretical approaches to chemical, biochemical, biophysical and cellular biology methods. Specifically, our program aims at (i) synthesizing original ligands as well as the tools that are required for receptor characterization; (ii) develop ligand:receptor 3D models to guide ligand synthesis; (iii) set up a totally original model system that will be composed of purified proteins that directly allow accurate molecular information on signaling to be obtained; (iv) develop an associated cellular model system that will allow us to put back this molecular data in a more integrated cellular context. This work will be carried out with the ghrelin receptor. This receptor has been selected here for several reasons: it is actually an important therapeutic target for treatment of disorders and disease such as obesity, growth hormone deficiency or diabetes; it is also a typical rhodopsin-like class A GPCR and therefore the mechanisms inferred from this system should be generalized to other members of this important class of GPCRs. It is expected from our program a clear molecular understanding to important aspects of GPCR functioning such as ligand- and dimerization-dependent regulation of signaling. In turn, this knowledge should have direct impacts on the development of both innovative drugs with reduced side effects and increased efficacy and original screening tools.