A nerve signal passes from one neuron to the next thanks to neurotransmitters, molecules that act on specific receptors located on the surface of the target neuron. Receptors dedicated to rapid transmission are composed of ion channels across the membrane. Upon binding of a neurotransmitter, the channel opens and ions enter (or exit) the cell, creating an electrical signal. Even though the function of these receptors (called Cys-loop) is well known, their molecular structure could only be explored in their bacterial counterparts until recently.
A team from the IBS and the laboratory of physical chemistry of polymers and membranes (EPFL, Switzerland)1 has just published the first complete structure of a mammalian (mouse) Cys-loop receptor: the 5-HT3 serotonin receptor. The researchers produced this protein in vitro using mammalian cells, and then blocked it in a specific conformation, thanks to llama antibodies. Once the molecule was crystallized, X-ray diffraction revealed the position and the organization of its amino acids2. The exterior binding site of serotonin and the ion channel resemble what is known from homologous structures. In contrast, the intracellular part, unique to mammals, had never before been seen. It is similar to a “hallway” with five lateral “doors”, which open or close by flexible loops.
This structure provides a framework for functional and pharmacological studies of the 5-HT3 receptor, which is a target (among others) for drugs against nausea induced by chemotherapy or anesthesia. The IBS researchers are interested in characterizing other conformations of the protein to better understand its dynamic properties, before applying the tools and methods developed to other Cys-loop receptors.
1 In collaboration with the following laboratories: architecture and function of biological macromolecules (CNRS/Université Aix-Marseille), structural dynamics of macromolecules (CNRS/Institut Pasteur), and the Théranyx society.
2 Amino acids are the building blocks of protein chains.