Cellular Physiology of Sensory Ion Channels

这项建议的长期目标是了解我们的神经系统是如何检测和处理 我们环境中的信息，并将这些环境刺激转化为电化学事件。我们的 方法是利用天然植物产品的药理作用，特别是那些能引起 刺激或不适，以揭示参与检测有害刺激的新信号机制 躯体感觉神经系统的神经元。事实上，这种方法在以下方面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，这些受体和酶对于检测和分析 调节产生疼痛的刺激，如使用阿司匹林等植物衍生产品所说明的那样， 吗啡、辣椒素和薄荷脑用于发现环生酶、阿片受体和温度敏感型色氨酸 频道，分别。 这项应用的一个主要焦点是确定芥末中辛辣的异硫氰酸酯化合物 植物(如山葵)通过激活TRPA1来兴奋感觉神经元，TRPA1是初级的兴奋通道 感觉神经元。目前尚不清楚这些药物如何作为TRPA1的选择性激动剂 频道。我们将使用遗传、化学和电生理方法的组合来解决这个问题 问题，对这些问题的答案应该提供对促进 激活和/或调节TRPA1。除了发挥“芥末受体”的作用外，TRPA1还可能起到作用。 与炎症产物，如缓激肽、组胺或5-羟色胺等刺激感官的机制有关 神经元。因此，我们的另一个目标是使用培养的来自正常和TRPA1缺陷的感觉神经元 以确定TRPA1是否参与这些兴奋作用，如果是，是什么细胞信号 机制是这一过程的基础。最后，我们还建议研究其他自然因素的影响。 关于培养感觉神经元的产品，目的是开发新的药理探针，用于 发现或表征重要的细胞信号机制，有助于检测或 感官刺激的调节。这些研究可能会促进新型止痛药的设计和开发 用于治疗外周疼痛综合征的药物，如关节炎或病毒性和糖尿病神经病变。

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.