Endogenous Activators of Vanilloid Receptor

描述（由申请人提供）： 辣椒素或香草素受体（VR）参与热的感觉， 和炎性疼痛。克隆（VR1）和天然VR是非选择性阳离子 通道直接激活有害热，细胞外质子和 香草素类化合物。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，这项研究已经获得了更多 考虑到VR1在非感觉组织中表达， 可能介导炎症而不是急性热痛。蛋白激酶C（PKC） 在疼痛信号中起着重要作用。PKC β蛋白的靶向缺失 小鼠显著减弱热和酸诱导的痛觉过敏。反过来， PKC β的激活增强感觉神经元中的热诱发电流。 此外，痛觉肽，缓激肽，增强热反应，诱导 去极化，并引起香草酸敏感神经元的分泌， PKC依赖的方式。然而，这些效应的分子靶点还没有被发现。 明确识别。在这项研究中，我们将测试的假设，VR是 在没有任何其他蛋白的情况下，直接被PKC介导的磷酸化激活。 激动剂我们认为促炎肽缓激肽诱导VR 活性，这是通过刺激PKC而发生的。我们还将测试 假设在磷酸化状态下，亚阈值刺激将被 足以最大限度地激活VR。我们认为， 通道用作增益控制，以调节 虚拟现实激活。通过这种方式，一系列正常的良性刺激将成为 VRs的有效激活剂。这项研究对以下方面具有重要意义： 了解VR在痛觉过敏，慢性疼痛和其他 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.