Structure and Function of TRPV channels

标题：TRPV通道的结构和功能 这项研究计划的长期目标是了解门控的分子机制， TRPV亚家族的两个重要生理学成员的细胞功能：瞬时受体电位 香草素2（TRPV 2）和瞬时受体电位香草素5（TRPV 5）。这些渠道属于同一个 TRP通道的亚家族，然而它们在组织分布、生理学上表现出显着差异 功能、细胞定位、离子渗透和选择性、通道门控机制和药理学。 TRPV 2是一种广泛表达的非选择性Ca ~（2+）离子通道，在神经元细胞内起着重要作用。 发育、免疫、心血管生理学和癌症。TRPV 5是一种高度选择性的钙离子通道， 仅在肾远曲小管上皮细胞的顶膜上表达， 在人体内Ca 2+稳态中的作用。这项建议是建立在我的小组所取得的重大进展之上的 在理解TRPV 2和TRPV 5通道的结构，门控和细胞功能的分子细节， 过去10年本提案的总体目标是进一步了解TRPV 2和TRPV 5通道是如何 在原子水平上通过内源性和外源性调节剂门控;并阐明TRPV 2通道精确 神经发育和免疫中的分子功能。为了回答这些问题，我们将采用切割- 边缘多学科的方法提供给我们的实验室，包括膜蛋白生物化学和 生物物理学，单粒子冷冻电镜，过氧化物酶催化的邻近标记和质谱，冷冻APEX 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性 通过电生理学和细胞生物学方法进行表征。这些信息对我们的 了解TRPV通道的生理和病理生理作用。

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.