Receptores Cys-loop: de estructura a patología

BOUZAT C

Cordoba

Conferencia; 1er Congreso conjunto de las Sociedades Argentinas de Biología; 2007

Ligand-gated ion channels, such as nicotinic (AChR) and serotonin 5HT3 receptors, mediate rapid responses throughout the nervous system. The molecular mechanism of activation is not known. However, its modification leads to pathological processes. To determine how the binding of agonist to the extracellular region is coupled to the opening of the ion pore, we constructed chimeric subunits combining the extracellular domains of the Acetylcholine Binding Protein or neuronal alpha7 AChR with the transmembrane region of 5HT3. The analysis of single-channel and macroscopic currents of the chimeric receptors revealed that a network of loops located at the interface between the binding and transmembrane domains allows functional connection between both domains and it governs the shape and strength of the synaptic response. C. elegans is a non mammalian model for the study of synaptic transmission, for testing drugs, and it is also a model of parasitic nematodes. Nematode muscle AChRs are targets for anthelmintic drugs, which act as potent agonists. We showed that, in contrast, they are partial agonists of mammalian AChRs, and we identified residues located at different faces of the binding site that govern the selectivity of anthelmintic drugs for AChR subtypes. We described for the first time at the single channel level the activation of C. elegans muscle AChRs by ACh and anthelmintic agents and showed functional changes in mutant worms.