Mechanosensitive Ion Channel Piezo1 Clustering Regulates Shearforce Perception

The sensing and responsing to mechanical stimuli is one of the most critical biological process of many organism.Piezo1 is the first mechanosensitive cation channel in mammals discovered that satisfied all four creteria of mechanosensitive ion channel.It can be activated by various mechanical stimulations and plays an important role in various organs of human body and embryonic development.Since its discovery in 2010,there are a large number of researches on its 3D structure,and its physiological properties,the mechanism of Piezo1 activation is still unclear.Our preliminary studies showed that,when Piezo1 was stimulated by increasing shear force,its activation doesn't increase monotonically.Based on the activation state of Piezo1 ion channel under continuous shear stress,we propose that the clustering of Piezo1 on the plasma membrane increases its sensitivity to shear force.This hypothesis explains its nonmonotonic resposes to shear force.The pattern of Piezo1 on the cell plasma membrane was studied at different spatial and temporal resolutions by two new methods:simultaneous TIRF and calcium life cell imaging,and dynamic cells fixationSTORM superresolution imaging.We found that,as the clusters were dispersed under high shearing force and reduced sensitivity to shear force,Piezo1 could not maintain the activation under continuous high-intensity shearing force stimulation.Our novel discovery that the piezo1 channel clustering increases its sensitivity to shear force,and high shear force disperse piezo1 cluster could be critical to understand how the piezo1 sensing shear force and regulate downstream signals.