Mechanisms of Heat Activation and Multimodal Functions of VR1 Receptor Channels

疼痛开始于外周神经末梢的特殊感觉神经元的传导， 伤害感受器了解这些伤害感受器如何对产生疼痛的刺激做出反应是迈向 理解疼痛的生物学这项研究涉及离子通道潜在的伤害，特别是， 克隆的香草素受体TRPV 1。最近对该通道的研究表明， 其功能和调节的复杂性水平，并涉及两者的检测和整合 外源性有害刺激如热、香草素和酸以及内源性促炎信号。的 该项目的目标是在分子水平上确定受体如何作为一种多功能的有毒物质发挥作用。 使用单通道电生理学方法响应各种刺激的检测器和积分器 结合分子生物学。第一个目标将集中在多模态激活的机制， 频道。提出实验来确定热敏感性是否需要由其他刺激 以激活通道以及不同模态的刺激如何在受体内相互作用。这项工作将 还开发了统一通道的多模态门控的变构模型。第二个目标是 研究多模态激活的结构基础。这项研究将检查门控在多大程度上 不同刺激的机制是分开的，并将描绘出对每个刺激特异的分子结构域。 刺激并决定其功能机制。第三个目标是脱敏， 恢复渠道。实验提出量化和建立的机制， TRPV 1激活引起的磷脂酰肌醇-45-二磷酸（PIP 2）耗竭，并阐明 脱敏状态的本质。这项拟议的研究将提高我们对伤害性感受的认识。 感觉传导，并将有利于疼痛治疗的临床进展，特别是，寻找止痛药 这些药物具有全新的作用模式和对伤害感受器前所未有的选择性。

Pain begins with transduction at peripheral nerve terminals of specialized sensory neurons called nociceptors. Understanding how these nociceptors respond to pain-producing stimuli is a key step towards understanding the biology of pain. This research concerns ion channels underlying nociception, in particular, the cloned vanilloid receptor TRPV1. Recent studies of the channel have shown a previously unsuspected level of complexity in its function and regulation and have implicated it in detection and integration of both exogenous noxious stimuli such as heat, vanilloids and acids and endogenous proinflammatory signals. The goal of the project is to determine, at the molecular level, how the receptor functions as a versatile noxious detector and integrator in response to various stimuli, using methods of single-channel electrophysiology combined with molecular biology. The first aim will focus on the mechanisms of the polymodal activation of the channel. Experiments are proposed to determine whether the heat sensitivity is required by other stimuli to activate the channel and how the stimuli of different modality interact within the receptor. The work will also develop allosteric models that unify the polymodal gating of the channel. The second objective is to investigate the structural basis of the polymodal activation. The study will examine to what extent the gating machinery for different stimuli are separated and will delineate the molecular domains specific to each stimulus and determine their functional mechanisms. The third aim concerns the desensitization and recovery of the channel. Experiments are proposed to quantify and establish the mechanisms of the depletion of phosphatidylinositol-45-bisphosphate (PIP2) caused by activation of TRPV1, and to elucidate the nature of the desensitized states. The proposed research will improve our knowledge of nociceptive sensory transduction and will benefit clinical advances in pain therapy, in particular, the search for analgesic drugs that have an entirely new mode of action and an unprecedented selectivity for nociceptors.