Structure and Function of TRPV channels

标题：TRPV通道的结构和功能 这项研究的长期目标是了解门控和门控的分子机制。 TRPV亚家族中两个重要生理成员的细胞功能：瞬时受体电位 香草素2(TRPV2)和瞬时受体电位香草素5(TRPV5)。这些频道属于相同的 Trp通道的亚家族，但它们在组织分布、生理 功能、细胞定位、离子渗透和选择性、通道门控机制和药理学。 TRPV2是广泛表达的钙离子通透性非选择性阳离子通道，在神经细胞中起重要作用。 发育、免疫、心血管生理学和癌症。TRPV5是一种高度选择性的钙通道， 仅在肾脏远曲小管上皮细胞的顶膜上表达，并发挥关键作用 在人体内钙动态平衡中的作用。这项建议是建立在我的小组取得的重大进展的基础上的 在理解TRPV2和TRPV5通道结构中，门控的分子细节和细胞功能 过去的10年里。本提案的总体目标是进一步了解TRPV2和TRPV5通道是如何 在原子水平上受内源和外源调节剂的调控，并阐明TRPV2通道的精确 神经发育和免疫中的分子功能。为了回答这些问题，我们将使用切割- 我们实验室提供的EDGE多学科方法，包括膜蛋白生物化学和 生物物理学，单粒子冷冻-EM，过氧化物酶催化的邻近标记和质谱学 用于电子显微镜成像、流式细胞术、共聚焦荧光显微镜和功能 通过电生理学和细胞生物学方法进行表征。这一信息在我们的 了解TRPV通道的生理和病理生理学作用。

Title: Structure and Function of TRPV channels The long-term objective of this research program is to understand the molecular mechanisms of gating and cellular function of the two physiologically important members of the TRPV subfamily: transient receptor potential vanilloid 2 (TRPV2) and transient receptor potential vanilloid 5 (TRPV5). These channels belong to the same subfamily of TRP channels, nevertheless they exhibit striking differences in their tissue distribution, physiological function, cellular localization, ion permeation and selectivity, mechanisms of channel gating and pharmacology. TRPV2 is broadly expressed Ca2+-permeable non-selective cation channel, which plays a vital role in neuronal development, immunity, cardiovascular physiology, and cancer. TRPV5 is a highly selective Ca2+ channel, that is only expressed on the apical membrane of kidney distal convoluted tubule epithelial cells and plays a critical role in Ca2+ homeostasis in the human body. This proposal is built on the major advances achieved by my group in understanding TRPV2 and TRPV5 channels structures, molecular details of gating and cellular function in the last 10 years. The overall goal of this proposal is to further understand how TRPV2 and TRPV5 channels are gated by endogenous and exogenous modulators at the atomic level; and to elucidate TRPV2 channel precise molecular function in neuronal development and immunity. To answer these questions, we will employ cutting- edge multidisciplinary approaches available to our laboratory, including membrane protein biochemistry and biophysics, single-particle cryo-EM, peroxidase-catalyzed proximity labeling and mass spectrometry, cryoAPEX for electron microscopy imaging, flow cytometry, confocal fluorescence microscopy, and functional characterization by electrophysiological and cell biological methods. This information would be critical in our understanding of TRPV channels physiological and pathophysiological roles.