Microscopic mechanism of PIEZO1 activation by pressure-induced membrane stretch.
Microscopic mechanism of PIEZO1 activation by pressure-induced membrane stretch.
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压力诱导膜拉伸活化PIEZO1的微观机制。
DOI：
10.1085/jgp.202213260
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发表时间：
2023-05-01
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--
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膜拉伸会激活机械敏感的 PIEZO1 通道，但这种刺激如何调节微观的打开和关闭状态以增加打开概率尚不清楚。在这里，Wijerathne 等人。使用单通道停留时间分析和马尔可夫链建模研究这种机制。机械敏感的 PIEZO1 离子通道响应膜拉伸而打开。然而，这种激活的潜在微观机制仍然未知。为了探究这一机制，我们使用细胞附着的压力钳记录来测量不同稳态负移液器压力下的单通道电流，涵盖通道压力灵敏度的整个范围。通过平均关闭持续时间的急剧减少和平均打开持续时间的适度增加来发生压力依赖性激活。在所有测试的压力中，打开和关闭停留时间的分布最好分别遵循两个和三个指数分量的总和。随着压力刺激幅度的增加，大多数指数分量的时间常数逐渐变化，打开和关闭停留时间的方向相反，并且变化程度相似。此外，虽然快速和慢速分量的相对幅度在打开间隔中保持不变，但在关闭间隔中它们完全相反，进一步减少了平均关闭持续时间。使用二维停留时间分析、马尔可夫链建模和模拟，我们确定了一个最小的五态模型，该模型概括了单通道数据的基本特征，包括微观可逆性、相邻打开和关闭间隔之间的相关性以及压力对停留时间的不对称调制。这项研究确定了压力诱导膜拉伸激活 PIEZO1 通道的微观机制，并加深了我们对 PIEZO 通道家族脊椎动物成员的机械传导的基本理解。
Membrane stretch activates mechanosensitive PIEZO1 channels, but how this stimulus modulates microscopic open and shut states to increase open probability is unknown. Here, Wijerathne et al. investigate this mechanism using single channel dwell time analysis and Markov-chain modeling. Mechanosensitive PIEZO1 ion channels open in response to membrane stretch. Yet, the underlying microscopic mechanism of this activation remains unknown. To probe this mechanism, we used cell-attached pressure-clamp recordings to measure single channel currents at different steady-state negative pipette pressures, spanning the full range of the channel’s pressure sensitivity. Pressure-dependent activation occurs through a sharp reduction of the mean shut duration and through a moderate increase of the mean open duration. Across all tested pressures, the distribution of open and shut dwell times best follows sums of two and three exponential components, respectively. As the magnitude of the pressure stimulus increases, the time constants of most of these exponential components gradually change, in opposite directions for open and shut dwell times, and to a similar extent. In addition, while the relative amplitudes of fast and slow components remain unchanged for open intervals, they fully reverse for shut intervals, further reducing the mean shut duration. Using two-dimensional dwell time analysis, Markov-chain modeling, and simulations, we identified a minimal five-states model which recapitulates essential characteristics of single channel data, including microscopic reversibility, correlations between adjacent open and shut intervals, and asymmetric modulation of dwell times by pressure. This study identifies a microscopic mechanism for the activation of PIEZO1 channels by pressure-induced membrane stretch and deepens our fundamental understanding of mechanotransduction by a vertebrate member of the PIEZO channel family.
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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
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