Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition
Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition
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DOI：
10.1038/35082088
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发表时间：
2001-06-21
期刊：
影响因子：
64.8
通讯作者：
Julius, D
中科院分区：
文献类型：
--
作者：
Chuang, HH;Prescott, ED;Julius, D
组织损伤产生内源性因素，通过增加感觉神经末梢对伤害性刺激的反应来增强我们的痛觉（1，2）。缓激肽和神经生长因子（NGF）是两种这样的促痛觉剂，其分别激活G蛋白偶联（BK 2）和酪氨酸激酶（TrkA）受体，以刺激初级传入神经元中的磷脂酶C（PLC）信号传导途径（3，4）。这些作用如何产生对物理或化学刺激的致敏性尚未在分子水平上阐明。在这里，我们表明，缓激肽或神经生长因子介导的增强热敏感性在体内需要VR 1的表达，热激活的离子通道的感觉神经元。通过抗体螯合或PLC介导的水解减少质膜磷脂酰肌醇-4，5-二磷酸（PtdIns（4，5）P-2）水平模拟缓激肽或NGF在细胞水平上的增强作用。此外，招聘PLC-γ TrkA是必要的神经生长因子介导的通道活性增强，和生化研究表明，VR 1与此复杂的。这些研究描绘了缓激肽和NGF产生超敏反应的生化机制，并可能解释PLC信号系统的激活如何调节TRP通道家族的其他成员。
Tissue injury generates endogenous factors that heighten our sense of pain by increasing the response of sensory nerve endings to noxious stimuli(1,2). Bradykinin and nerve growth factor (NGF) are two such pro-algesic agents that activate G-protein-coupled (BK2) and tyrosine kinase (TrkA) receptors, respectively, to stimulate phospholipase C (PLC) signalling pathways in primary afferent neurons(3,4). How these actions produce sensitization to physical or chemical stimuli has not been elucidated at the molecular level. Here, we show that bradykinin- or NGF-mediated potentiation of thermal sensitivity in vivo requires expression of VR1, a heat-activated ion channel on sensory neurons. Diminution of plasma membrane phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P-2) levels through antibody sequestration or PLC-mediated hydrolysis mimics the potentiating effects of bradykinin or NGF at the cellular level. Moreover, recruitment of PLC-gamma to TrkA is essential for NGF-mediated potentiation of channel activity, and biochemical studies suggest that VR1 associates with this complex. These studies delineate a biochemical mechanism through which bradykinin and NGF produce hypersensitivity and might explain how the activation of PLC signalling systems regulates other members of the TRP channel family.