Ion channels activated by mechanical inputs are important force sensing molecules in a wide array of mammalian cells and tissues. The transient receptor potential channel, TRPV4, is a polymodal, nonselective cation channel that can be activated by mechanical inputs but only if stimuli are applied directly at the interface between cells and their substrate, making this molecule a context-dependent force sensor. However, it remains unclear how TRPV4 is activated by mechanical inputs at the cell-substrate interface, which cell intrinsic and cell extrinsic parameters might modulate the mechanical activation of the channel and how mechanical activation differs from TRPV4 gating in response to other stimuli. Here we investigated the impact of substrate mechanics and cytoskeletal components on mechanically evoked TRPV4 currents and addressed how point mutations associated with TRPV4 phosphorylation and arthropathy influence mechanical activation of the channel. Our findings reveal distinct regulatory modulation of TRPV4 from the mechanically activated ion channel PIEZO1, suggesting the mechanosensitivity of these two channels is tuned in response to different parameters. Moreover, our data demonstrate that the effect of point mutations in TRPV4 on channel activation are profoundly dependent on the gating stimulus.

中文翻译：

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在细胞-基质界面调节 TRPV4 的机械活化

由机械输入激活的离子通道是多种哺乳动物细胞和组织中重要的力感应分子。瞬时受体电位通道 TRPV4 是一种多模态、非选择性阳离子通道，可以通过机械输入激活，但前提是刺激直接施加在细胞与其基质之间的界面上，使该分子成为上下文相关的力传感器。然而，目前尚不清楚 TRPV4 如何通过细胞 - 基质界面处的机械输入激活，哪些细胞内在和细胞外参数可能调节通道的机械激活，以及机械激活与 TRPV4 门控响应其他刺激有何不同。在这里，我们研究了底物力学和细胞骨架成分对机械诱发的 TRPV4 电流的影响，并解决了与 TRPV4 磷酸化和关节病相关的点突变如何影响通道的机械激活。我们的研究结果揭示了机械激活离子通道 PIEZO1 对 TRPV4 的不同调节，表明这两个通道的机械敏感性是根据不同参数进行调整的。此外，我们的数据表明 TRPV4 中的点突变对通道激活的影响在很大程度上取决于门控刺激。这表明这两个通道的机械敏感性是根据不同的参数进行调整的。此外，我们的数据表明 TRPV4 中的点突变对通道激活的影响在很大程度上取决于门控刺激。这表明这两个通道的机械敏感性是根据不同的参数进行调整的。此外，我们的数据表明 TRPV4 中的点突变对通道激活的影响在很大程度上取决于门控刺激。