Mechanism of physical force induced human slack channel desensitization

Human Slack (hSlack) channel is abundantly expressed in the central nervous system and regulates numerous physiological processes. Here, we identified hSlack channel is a voltage dependent physical force induced desensitization potassium channel. In the cell-attached mode, hSlack exhibited large voltage dependent potassium currents without significant delayed rectification or C-type inactivation. After breaking the cell membrane resulting the inside-out mode, the potassium currents were largely inhibited and it transited to the strong voltage dependent delayed rectified state. Structural results suggested that the "S6 site" confers the voltage dependent delayed rectification of hSlack channel, like our recent finding in hEag2 channel (In revision). Strikingly, the physical force induced desensitization and gating kinetics transition are mediated by the gatekeeper lipids in the central pore. Our results reported a novel physical force sensing channel through the pore lipids mediating physical force induced desensitization and gating kinetics transition. It opens a new door to understand the molecular basis of mechanobiology.