Lewis Amanda H, Cronin Marie E, Grandl Jörg
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
bioRxiv. 2024 May 29:2024.05.28.596257. doi: 10.1101/2024.05.28.596257.
Piezo1 is a mechanically activated ion channel that senses forces with short latency and high sensitivity. Piezos undergo large conformational changes, induce far-reaching deformation onto the membrane, and modulate the function of two-pore potassium (K2P) channels. Taken together, this led us to hypothesize that Piezos may be able to signal their conformational state to other nearby proteins. Here, we use chemical control to acutely restrict Piezo1 conformational flexibility and show that Piezo1 conformational changes, but not ion permeation through it, are required for modulating the K2P channel TREK1. Super-resolution imaging and stochastic simulations further reveal that both channels do not co-localize, which implies that modulation is not mediated through direct binding interactions; however, at high Piezo1 densities, most TREK1 channels are within the predicted Piezo1 membrane footprint, suggesting the footprint may underlie conformational signaling. We speculate that physiological roles originally attributed to Piezo1 ionotropic function could, alternatively, involve conformational signaling.
Piezo1是一种机械激活的离子通道，能够以短延迟和高灵敏度感知力。Piezo通道会发生大幅度的构象变化，在膜上引发深远的变形，并调节双孔钾离子（K2P）通道的功能。综合这些情况，我们推测Piezo通道或许能够将其构象状态传递给附近的其他蛋白质。在此，我们运用化学调控手段急性限制Piezo1的构象灵活性，结果表明，调节K2P通道TREK1需要Piezo1发生构象变化，而不是通过它进行离子渗透。超分辨率成像和随机模拟进一步揭示，这两种通道并不共定位，这意味着调节并非通过直接结合相互作用介导；然而，在Piezo1高密度时，大多数TREK1通道都处于预测的Piezo1膜覆盖范围内，这表明该覆盖范围可能是构象信号传递的基础。我们推测，最初归因于Piezo1离子otropic功能的生理作用，也可能涉及构象信号传递。 （注：原文中“ionotropic”可能有误，推测应为“ionotropic”，已按推测翻译，若有误请根据正确内容调整）
