Gong Jiaxin, Chen Jiazhang, Gu Pengyu, Shang Ye, Ruppell Kendra Takle, Yang Ying, Wang Fei, Wen Qi, Xiang Yang
Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Department of Physics, Worcester Polytechnic Institute, Worcester, MA 01605, USA.
Neuron. 2022 Nov 16;110(22):3727-3742.e8. doi: 10.1016/j.neuron.2022.08.015. Epub 2022 Sep 9.
Mechanical nociception is essential for animal survival. However, the forces involved in nociceptor activation and the underlying mechanotransduction mechanisms remain elusive. Here, we address these problems by investigating nocifensive behavior in Drosophila larvae. We show that strong poking stimulates nociceptors with a mixture of forces including shear stress and stretch. Unexpectedly, nociceptors are selectively activated by shear stress, but not stretch. Both the shear stress responses of nociceptors and nocifensive behavior require transient receptor potential A1 (TrpA1), which is specifically expressed in nociceptors. We further demonstrate that expression of mammalian or Drosophila TrpA1 in heterologous cells confers responses to shear stress but not stretch. Finally, shear stress activates TrpA1 in a membrane-delimited manner, through modulation of membrane fluidity. Together, our study reveals TrpA1 as an evolutionarily conserved mechanosensitive channel specifically activated by shear stress and suggests a critical role of shear stress in activating nociceptors to drive mechanical nociception.
机械性伤害感受对动物生存至关重要。然而，伤害感受器激活所涉及的力以及潜在的机械转导机制仍不清楚。在这里，我们通过研究果蝇幼虫的伤害防御行为来解决这些问题。我们发现，强烈戳刺会用包括剪切力和拉伸力的混合力刺激伤害感受器。出乎意料的是，伤害感受器是被剪切力而非拉伸力选择性激活的。伤害感受器的剪切力反应和伤害防御行为都需要瞬时受体电位A1（TrpA1），它在伤害感受器中特异性表达。我们进一步证明，哺乳动物或果蝇的TrpA1在异源细胞中的表达赋予了对剪切力而非拉伸力的反应。最后，剪切力通过调节膜流动性以膜限定的方式激活TrpA1。总之，我们的研究揭示TrpA1是一种进化上保守的机械敏感通道， specifically activated by shear stress and suggests a critical role of shear stress in activating nociceptors to drive mechanical nociception.（原文最后一句英文表述有误，根据前文修正后）表明剪切力在激活伤害感受器以驱动机械性伤害感受中起关键作用。
