In the brain, fast neurotransmission involves the release of neurotransmitters in the synapse, their binding to specific receptors, which then open and let ions flow over the postsynaptic membrane. The Cys-loop receptor family directly mediates this neurotransmission.
Cys-loop receptors are the targets of a legion of psycho-active and therapeutic compounds (including nicotine, alcohol, benzodiazepines, steroids, general anesthetics). More specifically, the family of -etron drugs are prominent antagonists of the 5-HT3 receptor, and widely used as anti-emetic drugs following chemotherapy or surgery. Therefore, the investigation into the structural mechanisms of these receptors can provide both fundamental biological insights and potential benefits to health.
The project proposes to describe and understand, through structure, the pharmacology and conformational transitions in the Cys-loop family of receptors, focusing first on the serotonin 5-HT3 receptor.
Starting with a solid body of preliminary results, we will first set up new expression and stabilization tools to facilitate structural studies. Then we will obtain high-resolution structures of the 5-HT3 receptor and of other mammalian receptors, taking advantage of crystallization chaperones. On the way, we will also investigate and engineer proteinic modulators of Cys-loop receptor function.
The proposed research will take place at the CNRS in Grenoble, France, in a very favorable environment for structural biology. The applicant is establishing his own group and bringing a new research theme to the host institute. The CIG grant will be instrumental in the success of the proposed research and in the career development of the applicant.
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