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

Cys环家族离子通道的结构-功能关系

• 批准号: 371702-2010
• 负责人: Campanucci, Veronica
• 金额: $ 2.77万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=528338
• 关键词: Structure; function; relationship; ion; channels

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.

神经元的功能是由离子通道的活动决定的，离子通道的调节可以促进或干扰神经系统的功能。该研究计划的长期目标是探索配体门控离子通道如何工作，并了解它们如何促进神经系统的功能。这项发现基金申请集中于5 -羟色胺能3型受体（5HT3R），作为Cys-loop受体家族的模型系统。特别是，我们将研究这些受体是如何工作的，它们是如何被调节的，以及它们在生理和病理氧化应激条件下如何参与自主神经系统的功能。拟制研究项目的短期目标在以下工作假设的范围内：(i)氧化应激诱导5HT3Rs进入长期失活状态；（ii）氧化应激期间5HT3Rs的失活是由位于受体胞内“口”的半胱氨酸残基氧化介导的；（iii） 5HT3Rs在调节交感神经节nachr的活动中起主要作用。我们的研究方法将利用啮齿动物模型和表达系统，辅以各种电生理、成像和分子技术。预计本研究将为氧化应激条件下配体门控离子通道活性的调控机制和5HT3Rs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。该计划将支持至少3名硕士或博士研究生的培训。