Molecular Pharmacology

G protein-coupled receptors (GPCR) represent the single largest family of cell surface receptors involved in signal transduction. In humans, it is estimated that several hundreds of distinct members direct responses to a wide variety of chemical transmitters, including biogenic amines, amino acids, peptides, lipids, nucleosides and large polypeptides. These transmembrane receptors are key controllers of such diverse physiological processes as neurotransmission, cellular metabolism, secretion, cellular differentiation and growth as well as inflammatory and immune responses. The GPCRs therefore represent major targets for the development of drug candidates with potential application in all clinical fields. In fact, close to 50% of the drugs prescribed today act by activating or blocking a GPCR. In recent years, increased knowledge about this class of receptor has facilitated the screening and development of many new therapeutically active molecules. Despite these successes, our ability to fully exploit the therapeutic potential of these receptors has been limited in part by our incomplete understanding of how GPCR signalling efficacy and selectivity are regulated.

Our research program focuses on the molecular mechanisms controlling the efficacy and the selectivity of GPCR signalling. For instance, several projects aim at describing, in molecular terms, the link between ligand binding and the signalling efficacy in specific signalling pathways. We study regulatory processes such as receptor phosphorylation, palmitoylation, ubiquitination and endocytosis that control hormonal responsiveness under normal and pathological conditions. Using various biochemical and biophysical approaches including resonance energy transfer techniques (BRET and FRET) we are exploring the role of protein-protein interactions in signal transduction by monitoring the real-time assembly of specific GPCR “signalosomes” in living cells. These studies led to the development of biosensors that allow exploring the functional selectivity of GPCRs with the goal of identifying new drugs with increased therapeutic efficacy and reduced undesirable effects.

In addition to investigate the dynamic regulation of the modules during signal transduction, we also study their biogenesis. In particular, we investigate genetic defects that leads to the misfolfing and improper targeting of GPCRs and result in pathologies known as conformational diseases. In this context we are developing pharmacological chaperones that can facilitate the proper maturation and cell trafficking of these GPCRs and hence represent new therapeutic avenues for the treatment of conformational diseases.

Through the knowledge gained, our studies have direct impacts on the development of innovative screening tools and new therapeutic approaches.

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