Endogenous Activators of Vanilloid Receptor

描述(由申请人提供)： 辣椒素或香草素受体(VRs)参与热感觉 和炎症性疼痛。克隆的(VR1)和天然的VRS是非选择性阳离子 由有毒热量直接激活的通道，细胞外质子和 香草类化合物。然而，相当多的注意力集中在确定 VR激活中的其他信号通路，这一研究取得了更多进展 VR1在非感觉组织和非感觉性组织中的表达 可能介导炎症性疼痛，而不是急性热痛。蛋白激酶C(PKC) 在疼痛信号中起着重要的作用。靶向缺失PKC epsilon in 小鼠能显著减轻热和酸引起的痛敏。反过来, PKC epsilon的激活增强了感觉神经元的热诱发电流。 此外，止痛肽，缓激肽，增强热反应，诱导 去极化和激发对香草素敏感的神经元的分泌 PKC依赖的方式。然而，这些效应的分子靶点并不是 身份明确的人。在这项研究中，我们将检验虚拟现实是 由PKC介导的磷酸化直接激活，而不存在任何其他 激动剂。我们认为促炎肽缓激肽可诱导VR 这是通过PKC的刺激而发生的。我们还将测试 假设在磷酸化状态下，亚阈值刺激将是 足以最大限度地激活VR。我们认为，该蛋白的磷酸化 通道起到增益控制的作用，以调节 VR激活。通过这种方式，一系列正常的良性刺激将成为 强大的血管紧张素转换酶激活剂。这项研究具有重要的意义 了解VRS在痛觉过敏、慢性疼痛和其他疾病中的作用 非感官功能。

DESCRIPTION (provided by applicant): Capsaicin or vanilloid receptors (VRs) participate in the sensation of thermal and inflammatory pain. The cloned (VR1) and native VRs are non-selective cation channels directly activated by noxious heat, extracellular protons and vanilloid compounds. However, considerable attention has focused on identifying other signaling pathways in VR activation, and this search has gained more significance given the findings that VR1 is expressed in non-sensory tissue and may mediate inflammatory rather than acute thermal pain. Protein kinase C (PKC) plays an important role in pain signaling. Targeted deletion of PKC epsilon in mice dramatically attenuates thermal- and acid-induced hyperalgesia. In turn, activation of PKC epsilon potentiates heat-evoked currents in sensory neurons. Further, the algesic peptide, bradykinin, potentiates heat responses, induces depolarization and evokes secretion from vanilloid-sensitive neurons in a PKC-dependent manner. Yet the molecular targets for these effects have not been clearly identified. In this study we will test the hypothesis that the VR is directly activated by PKC -mediated phosphorylation in the absence of any other agonist. We propose that the pro-inflammatory peptide bradykinin induces VR activity and that this occurs via the stimulation of PKC. We will also test the hypothesis that in the phosphorylated state, a subthreshold stimulus will be sufficient to maximally activate the VR. We propose that phosphorylation of the channel functions as a gain control to modulate the efficacy and sensitivity of VR activation. In this way a range of normally benign stimuli will become potent activators of VRs. This research has important implications for understanding the role of VRs in hyperalgesia, chronic pain and other non-sensory functions.