Structure-function relationship of ion channels from the Cys-loop family

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Neuronal function is determined by the activity of ion channels, and their modulation can contribute or interfere with the function of the nervous system. The long-term objectives of the proposed research program is to explore how ligand-gated ion channels work and understand how they contribute to the function of the nervous system. This Discovery Grant application concentrates on the serotoninergic type 3 receptor (5HT3R), as a model system for the Cys-loop family of receptors. Particularly, we will study how these receptors work, how they are modulated and how they participate in the function of the autonomic nervous system during physiological and pathological oxidative stress conditions. The short-term goals for the proposed research program fell in the scope of the following working hypothesis: (i) Oxidative stress induces 5HT3Rs to adopt a long-lasting inactivated state; (ii) The inactivation of 5HT3Rs during oxidative stress is mediated by the oxidation of cysteine residues located in the intracellular "mouth" of the receptor; and (iii) 5HT3Rs plays a major function fine tuning the activity of nAChRs in sympathetic ganglia. Our research approach will utilize rodent animal models and expression systems, complemented with a variety of electrophysiological, imaging and molecular techniques. It is anticipated that this research will provide a novel insight on the regulatory mechanisms of ligand-gated ion channel activity and the role of 5HT3Rs in autonomic function during oxidative stress conditions. These findings will constitute significant advances in the fields of ion channels, cell neurobiology and system neurophysiology. The proposed program will support the training of at least 3 graduate students at the M.Sc. or Ph.D. level.