Grant: Project Grant

The discovery and development of drugs with better therapeutic efficacy and lesser undesirable effects remains an unmet need for many clinical indications. Such endeavour requires a better understanding of the biology behind pathologies and of drug action. Many drugs work by regulating cell-to-cell communication (ex: neurotransmission and hormonal signalling). G protein-coupled receptors (GPCRs) represent the largest family of proteins involved in such cellular communication that transfers information from the outside to the inside of the cells. It is estimated that ˜ 30% of prescription drugs act through GPCRs. They are used for the management of many diseases, including: allergies, asthma, chronic pain, hypertension, migraine, schizophrenia, ulcers and many others. Yet, their potential is only superficially exploited, with less than 10% of the family members being targeted for their therapeutic value and with many of the existing GPCR drugs having less than optimal efficacy/side-effect profiles. This lack of success is in large part due to a deficient understanding of how receptors process and transduce the information. However, recent discoveries and technological developments have shed new light on the architecture and mechanisms of action of GPCRs, opening new research avenues that should provide the knowledge needed for the development of new and better drugs. Through the development of innovative imaging technologies and tool-compounds, the present proposal aims at better understanding how the information flows from GPCRs to the interior of the cells to control the physiological responses associated with specific diseases and therapeutic actions. Some of the GPCRs studied in our proposal are targets for the treatment of heart failure and type-2 diabetes. Therefore, in addition to provide fundamental knowledge applicable to the entire GPCR family, our work could pave the way for the discovery of innovative therapies for these diseases.