Acid potentiation of the capsaicin receptor determined by a key extracellular site
Acid potentiation of the capsaicin receptor determined by a key extracellular site
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DOI：
10.1073/pnas.100129497
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发表时间：
2000-07-05
影响因子：
11.1
通讯作者：
Julius, D
中科院分区：
文献类型：
--
作者：
Jordt, SE;Tominaga, M;Julius, D
辣椒素（类香草素）受体，VR1，是一种感觉神经元特异性离子通道，作为产生疼痛的化学和物理刺激的多模态检测器。VR1对辣椒素或有害热的反应在组织酸中毒期间遇到的pH范围内被细胞外质子动态增强，例如与关节炎、梗塞、肿瘤生长和其他形式的损伤相关的酸中毒。这一重要的生理活性的分子决定因素被定位到细胞外Glu残基（E600）的区域连接的第五跨膜结构域与推定的孔形成区域的通道。我们认为，这个残基作为一个关键的调节位点的受体，通过设置敏感性，其他有害的刺激在细胞外质子浓度的变化。我们还表明，质子，香草素，和热促进通道开放通过不同的途径，因为在第二个网站（E648）的突变选择性废除质子诱发的通道激活，而不减少对其他有害刺激的反应。我们的研究结果为VR1激活中的刺激特异性步骤提供了分子证据，并为开发新型镇痛剂提供了策略。
The capsaicin (vanilloid) receptor, VR1, is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. The response of VR1 to capsaicin or noxious heat is dynamically potentiated by extracellular protons within a pH range encountered during tissue acidosis, such as that associated with arthritis, infarction, tumor growth, and other forms of injury. A molecular determinant for this important physiological activity was localized to an extracellular Glu residue (E600) in the region linking the fifth transmembrane domain with the putative pore-forming region of the channel. We suggest that this residue serves as a key regulatory site of the receptor by setting sensitivity to other noxious stimuli in response to changes in extracellular proton concentration. We also demonstrate that protons, vanilloids, and heat promote channel opening through distinct pathways, because mutations at a second site (E648) selectively abrogate proton-evoked channel activation without diminishing responses to other noxious stimuli. Our findings provide molecular evidence for stimulus-specific steps in VR1 activation and offer strategies for the development of novel analgesic agents.