Membrane dome-based regulation mechanism of the mechanosensitive PIEZO channel

PIEZO channels are mechanosensitive ion channels essential for various physiological processes. How activation of PIEZO channels is regulated for distinct mechanical environments remains largely unclear. Here, we use patch-clamp electrophysiology to record pressure-activated currents of natural splicing isoforms of Caenorhabditis elegans PIEZO channels that differ in sequence length. These isoforms are sensitive in different tension regimes, consistent with the quantitative prediction from the membrane dome mechanism, based on structural measurement from cryo-electron microscopy data. Furthermore, these isoforms show different localization in the worm body and are involved in different physiological functions. Therefore, inspired by the membrane dome mechanism, a distinct regulatory strategy is found for PIEZO channels to tune the mechanosensitivity by adjusting the dome area via alternative splicing to adapt to the physiological environment.