Yoda1's energetic footprint on Piezo1 channels and its modulation by voltage and temperature.
Yoda1's energetic footprint on Piezo1 channels and its modulation by voltage and temperature.
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DOI：
10.1073/pnas.2202269119
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发表时间：
2022-07-19
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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机械敏感离子通道Piezo1发挥着许多重要的生理功能。这种重要的离子通道由一种名为 Yoda1 的合成小分子选择性激活。尽管目前正在努力开发具有潜在临床价值的 Yoda1 类似物，但 Yoda1 调节的 Piezo1 功能的性质和程度仍然未知。在这里，我们对 Yoda1 及其拮抗剂类似物 Dooku1 的作用进行了全面的生物物理表征。我们证明 Yoda1 通过分别在能量上稳定和破坏导电和非导电 Piezo1 构象来激活 Piezo1。我们进一步发现 Yoda1 的电生理效应强烈依赖于膜电位和温度，这两种已知的生理 Piezo1 调节剂。我们的研究阐明了 Piezo1 整合物理和化学线索的复杂性。 Piezo1 通道是脊椎动物中重要的机械激活离子通道。它们被合成化学激活剂 Yoda1 选择性激活，为探索其门控机制和开发新型药物开辟了新途径。然而，这种小分子调节 Piezo1 功能的性质和程度仍不清楚。在这里，我们通过对哺乳动物细胞中 Yoda1 对小鼠 Piezo1 的影响进行全面的生物物理学研究来缩小这一差距。使用钙成像，我们首先表明已知抑制机械诱发的 Piezo1 电流的半胱氨酸桥也抑制 Yoda1 的激活，这表明 Yoda1 通过大力调节机械感觉域发挥作用。 Yoda1 的存在改变了单通道停留时间和宏观动力学，与打开和关闭状态的双重和相互能量调制一致。至关重要的是，我们进一步发现 Yoda1 的电生理效应取决于膜电位和温度（另外两种 Piezo1 调节剂）。这项工作阐明了 Piezo1 通道的物理和化学调制器之间复杂的相互作用。
The mechanosensitive ion channel Piezo1 plays many important physiological functions. This essential ion channel is selectively activated by a synthetic small molecule called Yoda1. Despite current efforts to develop Yoda1 analogs with potential clinical value, the nature and extent of Piezo1 functions modulated by Yoda1 remain unknown. Here we performed a comprehensive biophysical characterization of the effects of Yoda1 and of its antagonist analog Dooku1. We show that Yoda1 activates Piezo1 by energetically stabilizing and destabilizing conducting and nonconducting Piezo1 conformations, respectively. We further discovered that the electrophysiological effects of Yoda1 strongly depend on membrane potential and temperature, two known physiological Piezo1 modulators. Our study illuminates the complexity by which Piezo1 integrates physical and chemical cues. Piezo1 channels are essential mechanically activated ion channels in vertebrates. Their selective activation by the synthetic chemical activator Yoda1 opened new avenues to probe their gating mechanisms and develop novel pharmaceuticals. Yet, the nature and extent of Piezo1 functions modulated by this small molecule remain unclear. Here we close this gap by conducting a comprehensive biophysical investigation of the effects of Yoda1 on mouse Piezo1 in mammalian cells. Using calcium imaging, we first show that cysteine bridges known to inhibit mechanically evoked Piezo1 currents also inhibit activation by Yoda1, suggesting Yoda1 acts by energetically modulating mechanosensory domains. The presence of Yoda1 alters single-channel dwell times and macroscopic kinetics consistent with a dual and reciprocal energetic modulation of open and shut states. Critically, we further discovered that the electrophysiological effects of Yoda1 depend on membrane potential and temperature, two other Piezo1 modulators. This work illuminates a complex interplay between physical and chemical modulators of Piezo1 channels.
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影响因子：
16.6
作者：
Cox CD;Bae C;Ziegler L;Hartley S;Nikolova-Krstevski V;Rohde PR;Ng CA;Sachs F;Gottlieb PA;Martinac B
通讯作者：
Martinac B
影响因子：
7.7
作者：
Guo YR;MacKinnon R
通讯作者：
MacKinnon R
离子通道温度依赖性门控的分子框架。
影响因子：
64.5
作者：
Chowdhury S;Jarecki BW;Chanda B
通讯作者：
Chanda B
影响因子：
7.7
作者：
Bai, Xiaofei;Bouffard, Jeff;Golden, Andy
通讯作者：
Golden, Andy
影响因子：
5.9
作者：
Jiang W;Del Rosario JS;Botello-Smith W;Zhao S;Lin YC;Zhang H;Lacroix J;Rohacs T;Luo YL
通讯作者：
Luo YL