Molecular Mechanism of pH Regulation of TRPV1 Activation

pH调节TRPV1激活的分子机制

• 批准号: 9053882
• 负责人: JIE ZHENG
• 金额: $ 6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053882
• 关键词: Address; Adopted; Affect; Afferent Neurons; Agonist; Binding; Binding Sites; Capsaicin; Chemicals; Clinical; Coupling; Development; Dose; Environment; Fluorescence; Fluorescence Resonance Energy Transfer; Fluorometry; Goals; Heating; Indium; Inflammation; Intervention; Investigation; Ion Channel; Ischemia; Kinetics; Knowledge; Ligands; Light; Measurement; Mediating; Methods; Molecular; Movement; Nature; Neurons; Optics; Pain; Pathway interactions; Phosphatidylinositol 4,5-Diphosphate; Physiological; Physiology; Play; Predisposition; Process; Proteins; Regulation; Relative (related person); Research; Role; Site; Stimulus; Structure; TRPV1 gene; Temperature; Testing; Thermodynamics; Tissues; base; design; extracellular; fluorophore; protonation; receptor; research study; response; sensor; tool; voltage

DESCRIPTION (provided by applicant): The heat sensor TRPV1 channel is a polymodal receptor that plays a key role in mediating neuronal pain caused by various noxious stimuli. One such stimulus is extracellular acidification caused by inflammation, tissue damage and ischemia. Low pH is thought to activate TRPV1 both directly by serving as a channel activator and indirectly by potentiating the channel's response to other stimuli. How TRPV1 activation is controlled by pH as well as its relation to activation by heat, ligands, and endogenous channel modulators remains largely unknown. Importantly, the highly unique susceptibility of TRPV1 activity to a variety of physical and chemical factors makes the channel an attractive target for clinical intervention of pain. The overarching goal of our research is to understand the cellular sensing function of TRPV1 by elucidating molecular mechanisms underlying its polymodal activation by heat, capsaicin and other stimuli. In the proposed study we aim to reveal the structural and mechanistic nature of extracellular H+ regulation of TRPV1. As H+-induced TRPV1 activity has heat-dependent and agonist-dependent components, this investigation will also shed light on how heat and agonist control TRPV1 activity. We approach our goal through a combination of optical, electrophysiological, and molecular methods. In particular, we will apply a patch fluorometry approach to directly observe structural changes in the channel protein or the binding of regulatory molecules, using fluorophores as molecular sensors. Simultaneous fluorescent and electrical recordings permit direct correlation of structural changes to their effects on channel activation. Using these methods, we will address questions on how changes in pH, temperature, and the concentration of agonists are sensed by TRPV1, what channel structures convey these stimuli, and how these stimuli converge to control TRPV1 activation. Answers to these questions should directly benefit the development of new clinical tools for treating TRPV1- mediated neuronal pain.

描述（由申请人提供）：热传感器TRPV1通道是一种多模式受体，在调节由各种有害刺激引起的神经元疼痛中发挥关键作用。其中一种刺激是由炎症、组织损伤和缺血引起的细胞外酸化。低 pH 值被认为可以通过充当通道激活剂来直接激活 TRPV1，也可以通过增强通道对其他刺激的反应来间接激活 TRPV1。 TRPV1 激活如何受 pH 控制以及它与热、配体和内源性通道调节剂激活的关系仍然很大程度上未知。重要的是，TRPV1 活性对多种物理和化学因素的高度独特的敏感性使得该通道成为临床疼痛干预的有吸引力的目标。我们研究的首要目标是通过阐明热、辣椒素和其他刺激下 TRPV1 多模式激活的分子机制来了解 TRPV1 的细胞传感功能。在本研究中，我们旨在揭示 TRPV1 细胞外 H+ 调节的结构和机制性质。由于 H+ 诱导的 TRPV1 活性具有热依赖性和激动剂依赖性成分，因此这项研究还将揭示热和激动剂如何控制 TRPV1 活性。我们通过结合光学、电生理学和分子方法来实现我们的目标。特别是，我们将应用贴片荧光测定方法，使用荧光团作为分子传感器，直接观察通道蛋白的结构变化或调节分子的结合。同时荧光和电记录允许结构变化与其对通道激活的影响直接相关。使用这些方法，我们将解决 TRPV1 如何感知 pH、温度和激动剂浓度的变化、哪些通道结构传递这些刺激以及这些刺激如何汇聚以控制 TRPV1 激活等问题。这些问题的答案应该直接有利于治疗 TRPV1 介导的神经元疼痛的新临床工具的开发。

项目成果

Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.

辣椒素结合和 TRPV1 离子通道激活的结构机制

• DOI: 10.1038/nchembio.1835
• 发表时间: 2015-07
• 期刊: NATURE CHEMICAL BIOLOGY
• 影响因子: 14.8
• 作者: Yang, Fan;Xiao, Xian;Cheng, Wei;Yang, Wei;Yu, Peilin;Song, Zhenzhen;Yarov-Yarovoy, Vladimir;Zheng, Jie
• 通讯作者: Zheng, Jie

Molecular mechanism of TRP channels.

• DOI: 10.1002/cphy.c120001
• 发表时间: 2013-01
• 期刊: Comprehensive Physiology
• 影响因子: 5.8
• 作者: Zheng J

Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations.

孔塔突变选择性破坏 TRPV1 通道的高灵敏度热激活，但不破坏辣椒素激活

• DOI: 10.1085/jgp.201110724
• 发表时间: 2012-04
• 期刊: The Journal of general physiology
• 作者: Cui Y;Yang F;Cao X;Yarov-Yarovoy V;Wang K;Zheng J
• 通讯作者: Zheng J

High temperature sensitivity is intrinsic to voltage-gated potassium channels.

• DOI: 10.7554/elife.03255
• 发表时间: 2014-07-16
• 期刊: eLife
• 影响因子: 7.7
• 作者: Yang F;Zheng J
• 通讯作者: Zheng J

A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1.

• DOI: 10.1038/ncomms9297
• 发表时间: 2015-09-30
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Yang S;Yang F;Wei N;Hong J;Li B;Luo L;Rong M;Yarov-Yarovoy V;Zheng J;Wang K;Lai R
• 通讯作者: Lai R