Cellular Physiology of Sensory Ion Channels

这项提案的长期目标是了解我们的神经系统如何检测和处理 信息在我们的环境中，并将这种环境刺激转换成电化学事件。我们 方法是利用天然植物产品的药理作用，特别是那些引起 刺激或不适，以揭示参与检测有害刺激的新型信号机制， 躯体感觉神经系统的神经元。事实上，这一方法已被证明是非常富有成效的， 细胞表面受体和酶的发现和分析对于检测和 调节产生疼痛的刺激，如使用植物衍生产品如阿司匹林， 吗啡、辣椒素和薄荷醇，发现环化酶、阿片受体和热敏TRP 渠道，分别。 本申请的一个主要重点是确定如何辛辣的异硫氰酸酯化合物从芥末 植物（如山葵）通过激活TRPA 1（初级神经元上的兴奋性通道）来兴奋感觉神经元。 感觉神经元目前尚不清楚这些药物如何作为TRPA 1的选择性激动剂 频道我们将使用遗传学、化学和电生理学的方法来解决这个问题 这一问题的答案应能提供对促进发展的内源性机制的重要见解。 TRPA 1的激活和/或调节。除了作为“山葵受体”，TRPA 1可能有助于 与炎症产物如缓激肽、组胺或缓激肽刺激感觉神经元的机制有关， 神经元因此，我们的另一个目标是使用来自正常和TRPA 1缺陷的培养感觉神经元， 小鼠，以确定TRPA 1是否有助于这些兴奋性行为，如果是这样，什么细胞信号 这一过程的基础机制。最后，我们还建议研究其他自然因素的影响。 产品在培养的感觉神经元，目的是开发新的药理学探针， 发现或表征有助于检测的重要细胞信号传导机制，或 对感官刺激的调节。这些研究可能促进新型镇痛药的设计和开发 用于治疗外周疼痛综合征如关节炎或病毒性和糖尿病性神经病的药物。

The long-term objective of this proposal is to understand how our nervous system detects and processes information in our environment and transduces such environmental stimuli into electrochemical events. Our approach is to exploit the pharmacological power of natural plant products, specifically those that elicit irritation or discomfort, to uncover novel signaling mechanisms involved in the detection of noxious stimuli by neurons of the somatosensory nervous system. Indeed, this approach has proven to be extremely fruitful in the discovery and analysis of cell surface receptors and enzymes that are important for the detection and modulation of pain-producing stimuli, as illustrated by the use of plant-derived products such as aspirin, morphine, capsaicin, and menthol to discover cycloogenases, opiate receptors, and thermosensitive TRP channels, respectively. A major focus of this application is to determine how pungent isothiocyanate compounds from mustard plants (such as wasabi) excite sensory neurons by activating TRPA1, an excitatory channel on primary sensory neurons. It is currently unknown how these agents serve as selective agonists for the TRPA1 channel. We will use a combination of genetic, chemical, and electrophysiological methods to address this question, answers to which should provide significant insight into endogenous mechanisms that promote the activation and/or modulation of TRPA1. In addition to serving as a "wasabi receptor", TRPA1 may contribute to the mechanism whereby inflammatory products, such as bradykinin, histamine, or serotinin excite sensory neurons. Thus, another of our aims is to use cultured sensory neurons from normal and TRPA1-deficient mice to determine whether TRPA1 contributes to these excitatory actions and, if so, what cellular signaling mechanisms underlie this process. Finally, we are also proposing to examine effects of other natural products on cultured sensory neurons with the aim of developing novel pharmacological probes with which to discover or characterize important cellular signaling mechanisms that contribute to the detection or modulation of sensory stimuli. These studies may stimulate the design and development of novel analgesic agents for treating peripheral pain syndromes, such as arthritis or viral and diabetic neuropathies.