Cellular Physiology of Sensory Ion Channels

该提案的长期目标是了解我们的神经系统如何检测和处理 我们的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功效，特别是那些能够引起 刺激或不适，以揭示涉及检测有害刺激的新信号传导机制 体感神经系统的神经元。事实上，这种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分析非常重要 调节产生疼痛的刺激，如使用阿司匹林等植物衍生产品所示， 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。 该应用的一个主要重点是确定芥末中异硫氰酸酯化合物的刺激性如何 植物（如芥末）通过激活 TRPA1（初级上皮细胞的兴奋通道）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 TRPA1 的选择性激动剂 频道。我们将结合使用遗传、化学和电生理学方法来解决这个问题 问题的答案应该提供对促进内生机制的重要见解 TRPA1 的激活和/或调节。除了充当“芥末受体”之外，TRPA1 还可能有助于 缓激肽、组胺或血清素等炎症产物刺激感觉的机制 神经元。因此，我们的另一个目标是使用来自正常和 TRPA1 缺陷的培养感觉神经元 小鼠以确定 TRPA1 是否有助于这些兴奋作用，如果是的话，是什么细胞信号传导 机制是这一过程的基础。最后，我们还建议检查其他自然因素的影响 产品针对培养的感觉神经元，旨在开发新型药理学探针 发现或表征重要的细胞信号传导机制，有助于检测或 感觉刺激的调节。这些研究可能会刺激新型镇痛药的设计和开发 用于治疗外周疼痛综合征，例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.