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

神经元功能由离子通道的活动决定，它们的调节可以促进或干扰神经系统的功能。拟议研究计划的长期目标是探索配体门控离子通道的工作原理并了解它们如何促进神经系统的功能。该发现资助申请重点关注 3 型血清素能受体 (5HT3R)，作为 Cys 环受体家族的模型系统。特别是，我们将研究这些受体在生理和病理氧化应激条件下如何工作、如何调节以及如何参与自主神经系统的功能。拟议研究计划的短期目标属于以下工作假设的范围：（i）氧化应激诱导 5HT3Rs 采取持久的失活状态； (ii) 氧化应激期间 5HT3R 的失活是由位于受体细胞内“口”的半胱氨酸残基的氧化介导的； (iii) 5HT3Rs 在微调交感神经节中 nAChRs 的活性方面发挥着主要功能。我们的研究方法将利用啮齿动物模型和表达系统，并辅以各种电生理学、成像和分子技术。预计这项研究将为配体门控离子通道活性的调节机制以及氧化应激条件下 5HT3R 在自主神经功能中的作用提供新的见解。这些发现将构成离子通道、细胞神经生物学和系统神经生理学领域的重大进展。拟议的计划将支持至少 3 名硕士研究生的培训。或博士学位等级。

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.