Mechanical memory of excitable cells induced by mechanosensitive channel inactivation

Recent experiments have unveiled a fascinating phenomenon: excitable cells exhibit mechanical memory, whereby their present excitation behaviors strongly depend on their past mechanical experiences. However, the underlying mechanism of this phenomenon remains elusive. Here, we introduce an electromechanical framework that integrates mechanical cell deformation, state transformations of mechanosensitive (MS) channels (such as Piezo channels), and transmembrane ion fluxes. We reveal that MS channel inactivation yields history-dependent excitation dynamics, characterized by a progressive decline in subsequent activated currents with increasing amplitude, speed, and duration of prior mechanical stimuli. Moreover, MS channel inactivation in preceding stimulation results in a refractory period during which cells cannot elicit new action potentials upon subsequent mechanical stimuli. Finally, we show that cells can adapt to preceding mechanical stimulation due to inactivation of MS channels, resulting in a higher activated threshold stimulation. Thus, MS channel inactivation favors the reduction of firing activities in response to prolonged and repeated mechanical stimuli ("neural adaptation"), which may protect neurons against overactivation and damage. We then conduct two virtual experiments to predict how changes in mechanical properties of neurons modify their excitation behaviors. These findings together emphasize a critical role of MS channel inactivation in governing the mechanical memory and neural adaptation of excitable cells, shedding new light on the intricate interplay between mechanical forces and cellular electrical responses.