Nature:诺奖得主揭示离子通道分子Piezo 1转导机械性痒觉信息

2022-06-28 周科 “神经周K”公众号

Piezo1蛋白在调控痒觉超敏和慢性痒觉异常中的关键作用

瘙痒感觉引起抓挠行为,这是一种行为防御机制,有助于清除有害刺激物。瘙痒是皮肤病最为常见的症状之一最为人所知引起瘙痒的化学性物质为组胺,受到过敏刺激或蚊虫叮咬后从肥大细胞中释放出来。此外还存在肠血管活性肽、P物质等非组胺物质引起痒觉。

背根神经节(DRG)和三叉神经节内体感神经元群选择性地驱动小鼠的化学性瘙痒行为。单细胞测序揭示了化学瘙痒感受器主要表达生长抑素 (Sst) 、MAS相关的G蛋白藕联受体A3(Mrgpra3)和利钠肽前体 B (Nppb)。组胺注射到小鼠和人类皮肤后产生对机械性瘙痒的超敏反应(痒觉异化)。Nppb和Mrgpra3阳性DRG神经元在上述过程中被激活。

美国科学家大卫·朱利叶斯(David Julius)和阿登·帕塔普蒂安(Ardem Patapoutian)因在感受温度和触觉方面的发现获得2021年诺贝尔生理学或医学奖。他们确定了三个离子通道(TRPV1、TRPM8 和 Piezo )感知温度或机械刺激相关的许多生理功能。

机械性瘙痒可由羊毛纤维或爬行昆虫等轻触诱发。在激活Toll样受体5阳性Aβ-低阈值机械感受器或抑制脊髓区域接受阈值机械感受器输入神经肽Y阳性抑制性中间神经元诱发机械性痒觉。

2022年6月22日美国斯克利普斯研究所Ardem Patapoutian研究团队揭示了背根神经节感觉神经元中介导机械力感知的分子受体PIEZO1蛋白调控机械性痒觉。

图1:Piezo1表达在痒觉受体神经元

原位杂交实验发现92%Piezo1表达在Nppb阳性DRG神经元,但几乎不表达在Mrgpra3阳性神经元中,而小部分Piezo2表达在该类型神经元上。Piezo1表达在与机械性疼痛和化学性瘙痒有关的MAS相关G蛋白偶联受体D(Mrgprd)阳性神经元。

通过离体电生理记录发现敲低Piezo1表达后能够明显减少DRG神经元对机械刺激的响应,在敲低Piezo2并不不会出现上述明显的抑制作用,而在同时敲低Piezo1和Piezo2后,几乎所有的DRG神经元对机械刺激的不响应。

特异性敲除外周感觉神经元上的Piezo1(后续简称外周Piezo1敲除小鼠)或特异性敲除Nppb阳性DRG神经元上的Piezo1后,在机械性瘙痒模型中可明显降低小鼠的抓挠行为,抓伤区域减少。此外,组胺引起的痒觉异化模型中上述两种类型敲除小鼠依然出现抓伤,但抓挠行为明显减少。

图2:敲除Piezo1后小鼠痒觉异常

在注射激活Piezo1的小分子Yoda1可诱发小鼠明显的抓伤,在敲除外周感觉神经元Piezo1后可阻断Yoda1诱发的痒觉。另一方面,通过基因功能获得技术构建PIEZO1增强模型小鼠后在机械性刺激后痒觉明显增加,也能增强Yoda1诱发的痒觉效应,这些结果表明Piezo1调控机械性痒觉。

人类过敏性皮肤炎是最常见的慢性痒觉异常。正常小鼠在服用维生素D类似物MC903后可诱发颈背、耳朵或脸颊的搔痒,痒觉超敏性,模拟慢性痒觉异常。但在敲除外周感觉神经元Piezo1后并不会出现痒觉异常。

GsMTx4 是一种蜘蛛毒液肽,可选择性地抑制Piezo1活性。研究人员发现GsMTx4 可明显降低机械性刺激引起的抓挠行为,也明显减弱慢性痒觉异常小鼠的痒觉超敏性。

总的来说,本文揭示了Piezo1蛋白在调控痒觉超敏和慢性痒觉异常中的关键作用。

原始出处:

Hill, R.Z., Loud, M.C., Dubin, A.E. et al. PIEZO1 transduces mechanical itch in mice. Nature (2022). https://doi.org/10.1038/s41586-022-04860-5.

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    2022-10-19 liye789132251
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    2022-06-29 wumeihua90
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    2022-06-28 学医无涯

    了解一下

    0

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    2022-06-28 xulv123

    认真学习~

    0

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