Michel Bouvier and his team study G-protein coupled receptors (GPCRs), a family of proteins that play a key role in controlling many biological processes and that make up a prime target for developing new drugs.
G protein-coupled receptors (GPCRs) represent the single largest family of cell surface receptors involved in signal transduction. In humans, several hundred of them regulate various biological processes such as neurotransmission, metabolism, cellular growth, immune and inflammatory responses, olfaction and vision.
By better understanding the internal mechanics of these receptors, along with the signalling pathways that they activate, it will be possible to improve the effectiveness of existing drugs as well as to develop new therapeutic molecules to fight several clinical indications, including innovative strategies to treat cancer.
Michel Bouvier’s team strives to understand, in great detail, what are the molecular mechanisms controlling the effectiveness and the selectivity of GPCR signalling. They are particularly interested in the role of protein-protein interactions in GPCR signal transduction. They discovered that, contrary to what was originally believed, a given GPCR controls the activity of many intracellular effectors and that different drugs can regulate distinct subsets of these effectors (biased signaling), opening the possibility of developing drugs that would trigger the beneficial responses while avoiding the harmful side effects.
They develop and use biochemical and biophysical approaches, such as bioluminescence resonance energy transfer (BRET), to study the spatio-temporal propagation of signaling in living cells to assess the molecular and structural determinants of GPCR functional selectivity and biased signaling.
Along with studying the dynamic regulation of GPCRs, the team also focuses on the genetic defects that result in their malfunction, notably mutant GPCRs responsible for what are known as “conformational diseases”. They are currently developing pharmacological chaperones able to compensate for the impact of the mutation, and facilitate the folding, maturation and trafficking of the GPCRs in order to restore their function.