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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