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Irritant-evoked activation and calcium modulation of the TRPA1 receptor

机译：TRPA1受体的刺激诱发活化和钙调制

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摘要

The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids(1). TRPA1 is also a 'receptor-operated' channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch, making it an attractive target for novel analgesic therapies(2). However, the mechanisms by which TRPA1 recognizes and responds to electrophiles or cytoplasmic second messengers remain unknown. Here we use strutural studies and electrophysiology to show that electrophiles act through a two-step process in which modification of a highly reactive cysteine residue (C621) promotes reorientation of a cytoplasmic loop to enhance nucleophilicity and modification of a nearby cysteine (C665), thereby stabilizing the loop in an activating configuration. These actions modulate two restrictions controlling ion permeation, including widening of the selectivity filter to enhance calcium permeability and opening of a canonical gate at the cytoplasmic end of the pore. We propose a model to explain functional coupling between electrophile action and these control points. We also characterize a calcium-binding pocket that is highly conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization and activation by metabotropic receptors. These findings provide a structural framework for understanding how a broad-spectrum irritant receptor is controlled by endogenous and exogenous agents that elicit or exacerbate pain and itch.
机译：瞬态受体电位离子通道TRPA1由初级传入神经纤维表达，其中它用作用于结构性不同的亲电子刺激物的低阈值传感器，包括小挥发性环境毒物和内源性抗腓原糖（1）。 TRPA1也是一种“受体操作”通道，其在代谢性受体下游激活引发炎症疼痛或瘙痒，使其成为新型镇痛治疗（2）的有吸引力的靶标。然而，TRPA1识别和响应电子特药物或细胞质第二信使的机制仍然未知。在这里，我们使用质量研究和电生理学表明，电子手机通过两步过程起作用，其中高反应性半胱氨酸残基（C621）的修饰促进细胞质回路的重新定位，以增强附近半胱氨酸的亲核和修饰，从而提高了附近半胱氨酸的亲核性和改性以激活配置稳定环路。这些动作调节了控制离子渗透的两个限制，包括选择性过滤器的加宽，以增强孔的细胞质末端的钙渗透性和打开规范栅极。我们提出了一种模型来解释电子手术和这些控制点之间的功能耦合。我们还表征了一种钙粘合袋，其在TRP通道亚型中高度保守，并且占钙依赖性TRPA1调节的所有方面，包括通过代谢受体的增强，脱敏和激活。这些发现提供了一种结构框架，了解广谱刺激受体如何通过引发或加剧疼痛和瘙痒的内源和外源剂来控制。

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  • 来源
    《Nature》 |2020年第7823期|141-145|共5页
  • 作者

    Zhao Jianhua; King John V. Lin; Paulsen Candice E.; Cheng Yifan; Julius David;

  • 作者单位

    Univ Calif San Francisco Dept Biochem & Biophys San Francisco CA 94143 USA|Yale Sch Med Dept Mol Biophys & Biochem New Haven CT USA;

    Univ Calif San Francisco Howard Hughes Med Inst San Francisco CA 94117 USA|Univ Calif San Francisco Dept Physiol Box 0444 San Francisco CA USA;

    Univ Calif San Francisco Howard Hughes Med Inst San Francisco CA 94117 USA|Univ Calif San Francisco Neurosci Grad Program San Francisco CA 94143 USA;

    Univ Calif San Francisco Dept Biochem & Biophys San Francisco CA 94143 USA;

    Univ Calif San Francisco Howard Hughes Med Inst San Francisco CA 94117 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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