Structural Insights into TRPV Channel Gating

项目总结/摘要(家长奖) 瞬时受体电位(Trp)通道在人体生理和免疫功能中发挥着重要作用 促进必需离子(钠、钙)透过质膜。这件事的重点是 关于瞬时受体电位香草素2(TRPV2)的提出，它起着至关重要的作用 在心功能和免疫力方面，已被列入重要抗肿瘤药物名单 目标。然而，在细胞和分子水平上，它仍然是研究最少的trpv通道。 级别。我们建议使用冷冻-EM、电生理分析、定点分析相结合 突变，以及建立详细的结构理解的计算方法 TRPV2通道选通的机制。在当前的提案中，我们将重点了解 肌醇磷脂对TRPV2的调节，通过多种途径确定TRPV2的门控机制 并剖析了TRPV2与细胞骨架相互作用的分子机制。信息 完成这些研究后得到的数据将有可能用于未来的TRPV2的设计 特效治疗学

PROJECT SUMMARY/ABSTRACT (parent award) Transient receptor potential (TRP) channels play significant roles in human physiology and facilitate essential ions’ (Na+, Ca2+) permeation through the plasma membrane. The focus of this proposal is on the transient receptor potential vanilloid 2 (TRPV2), which plays an essential role in cardiac function and immunity, and has been placed on the list of important anti-tumor drug targets. Nevertheless, it remains the least studied TRPV channel at the cellular and molecular levels. We propose to use the combination of cryo-EM, electrophysiological analysis, site-directed mutagenesis, and computational methods to establish a detailed structural understanding of the mechanisms of TRPV2 channel gating. In this current proposal we will focus on understanding TRPV2 regulation by phosphoinositides, determine the mechanism of TRPV2 gating by diverse ligands and dissect the molecular mechanism of TRPV2 interaction with cytoskeleton. Information obtained upon completion of these studies will be potentially used for future design of TRPV2 specific therapeutics