小柯机器人

美国加州大学David Julius和Yifan Cheng课题组研究揭示了TRPA1受体在刺激性激活和钙调节过程中的功能。2020年7月6日出版的《自然》杂志在线发表了这一成果。

研究人员使用结构研究和电生理学证明了亲电试剂通过两步过程起作用，其中高反应性半胱氨酸残基（C621）的修饰促进细胞质环的重新定向，增强亲核性并增强附近半胱氨酸（C665）的修饰，从而在激活配置中稳定环路。这些作用调整了控制离子渗透的两个限制，包括加宽选择性过滤器以增强钙离子的渗透性和在细胞质孔末端开启典型门通道。

研究人员提出一个模型来解释亲电作用和这些控制点之间的功能耦合。研究还发现了一个钙离子结合袋，该结合袋在整个TRP通道亚型中高度保守，并解释了钙依赖性TRPA1调控的所有方面，包括增强、脱敏和代谢型受体激活。这些发现为理解广谱刺激性受体如何响应内源性或外源性试剂引起或加剧疼痛和瘙痒提供了新思路。

据悉，瞬时受体电位离子通道TRPA1由初级传入神经纤维表达，其作为低阈值传感器，用于结构多样的亲电刺激物，其中包括环境中小的挥发性毒物和内源产生疼痛的脂质。TRPA1也是一个“受体操纵”的通道，其在促代谢受体下游的激活引起炎症性疼痛或瘙痒，使其成为新型镇痛药的潜在靶点。但是，TRPA1识别并响应亲电试剂或细胞质第二信使的机制仍然未知。

附：英文原文

Title: Irritant-evoked activation and calcium modulation of the TRPA1 receptor

Author: Jianhua Zhao, John V. Lin King, Candice E. Paulsen, Yifan Cheng, David Julius

Issue&Volume: 2020-07-08

Abstract: 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 lipids1. 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 therapies2. 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.

DOI: 10.1038/s41586-020-2480-9

Source: https://www.nature.com/articles/s41586-020-2480-9

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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