Cellular Physiology of Sensory Ion Channels

感觉离子通道的细胞生理学

• 批准号: 7637776
• 负责人: David Julius
• 金额: $ 33.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637776
• 关键词: Address; Afferent Neurons; Agonist; Amplifiers; Analgesics; Arthritis; Aspirin; Biochemical; Biological Factors; Bradykinin; Calcium; Caliber; Capsaicin; Cell Surface Receptors; Cell physiology; Cells; Chemical Agents; Chemicals; Deer; Detection; Development; Diabetic Neuropathies; Environment; Enzymes; Esthesia; Event; Fractionation; Goals; Hand; Heating; Histamine; Hyperalgesia; Image; Inflammatory; Ion Channel; Irritants; Isothiocyanates; Laboratories; Light; Mediating; Menthol; Methods; Molecular; Molecular Genetics; Molecular Target; Morphine; Mus; Mustard Plant; Nervous system structure; Neurogenic Inflammation; Neurons; Nociceptors; Opioid Receptor; Pain; Peripheral; Physiological; Plants; Process; Production; Psychophysiology; Research Personnel; Role; Sensory; Sensory Nerve Endings; Sensory Process; Serotonin; Shock; Signal Transduction; Squirrel; Stimulus; Syndrome; System; TRP channel; TRPA1 Channel; Testing; Trigeminal System; Viral; allyl isothiocyanate; chemical genetics; design; expression cloning; in vivo; information processing; insight; irritation; mustard oil; novel; patch clamp; programs; receptor; receptor coupling; receptor operated channel; research study; response; sanshool; sensory stimulus; somatosensory; tool; ward

DESCRIPTION (provided by applicant): 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 serotonin 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.

描述（由申请人提供）：本提案的长期目标是了解我们的神经系统如何检测和处理环境中的信息，并将这些环境刺激转换为电化学事件。我们的方法是利用天然植物产品的药理作用，特别是那些引起刺激或不适，发现新的信号转导机制参与检测有害刺激的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，是重要的检测和调节疼痛产生的刺激，如使用植物衍生的产品，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通道，分别说明。本申请的一个主要焦点是确定来自芥菜植物（如山葵）的辛辣异硫氰酸酯化合物如何通过激活初级感觉神经元上的兴奋性通道TRPA 1来兴奋感觉神经元。目前尚不清楚这些药物如何作为TRPA 1通道的选择性激动剂。我们将使用遗传，化学和电生理学方法的组合来解决这个问题，答案应该提供显着的洞察内源性机制，促进激活和/或调节TRPA 1。除了作为“芥末受体”，TRPA 1可能有助于炎症产物，如缓激肽，组胺或血清素兴奋感觉神经元的机制。因此，我们的另一个目标是使用培养的感觉神经元从正常和TRPA 1缺陷的小鼠，以确定是否TRPA 1有助于这些兴奋性的行动，如果是这样的话，什么细胞信号传导机制的基础上这一过程。最后，我们还建议研究其他天然产物对培养的感觉神经元的影响，目的是开发新的药理学探针，以发现或表征有助于检测或调节感觉刺激的重要细胞信号传导机制。这些研究可能会刺激设计和开发新的止痛剂治疗外周疼痛综合征，如关节炎或病毒和糖尿病神经病变。