Piezo1 belongs to mechano-activatable cation channels serving as biological force sensors. However, the molecular events downstream of Piezo1 activation remain unclear. In this study, we used biosensors based on fluorescence resonance energy transfer (FRET) to investigate the dynamic modes of Piezo1-mediated signaling and revealed a bimodal pattern of Piezo1-induced intracellular calcium signaling. Laser-induced shockwaves (LIS) and its associated shear stress can mechanically activate Piezo1 to induce transient intracellular calcium (Ca_[i]) elevation, accompanied by an increase in FAK activity. Interestingly, multiple pulses of shockwave stimulation caused a more sustained calcium increase and a decrease in FAK activity. Similarly, tuning the degree of Piezo1 activation by titrating either the dosage of Piezo1 ligand Yoda1 or the expression level of Piezo1 produced a similar bimodal pattern of FAK responses. Further investigations revealed that SHP2 serves as an intermediate regulator mediating this bimodal pattern in Piezo1 sensing and signaling. These results suggest that the degrees of Piezo1 activation induced by both mechanical LIS and chemical ligand stimulation may determine downstream signaling characteristics.

中文翻译：

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机械传感器 Piezo1 介导细胞内钙和 FAK 信号传导的双峰模式

Piezo1 属于机械可激活的阳离子通道，用作生物力传感器。然而，Piezo1 激活下游的分子事件仍不清楚。在本研究中，我们使用基于荧光共振能量转移（FRET）的生物传感器来研究 Piezo1 介导的信号传导的动态模式，并揭示了 Piezo1 诱导的细胞内钙信号传导的双峰模式。激光诱导冲击波 (LIS) 及其相关剪切应力可以机械激活 Piezo1 诱导瞬时细胞内钙 (Ca _[i]) 升高，伴随着 FAK 活性的增加。有趣的是，多次冲击波刺激脉冲导致钙离子更持续增加，FAK 活性降低。类似地，通过滴定 Piezo1 配体 Yoda1 的剂量或 Piezo1 的表达水平来调整 Piezo1 激活程度，产生了类似的 FAK 响应双峰模式。进一步的研究表明，SHP2 作为中间调节器介导 Piezo1 传感和信号传导中的这种双峰模式。这些结果表明机械 LIS 和化学配体刺激诱导的 Piezo1 激活程度可能决定下游信号传导特征。