Understanding force sensing mechanisms in mechanosensitive Piezo channels

Cox CD*, Bavi N and Martinac B

Victor Chang Cardiac Research Institute.

Mechanosensitive channels are essential molecular components of mechanosensory systems in all organisms. Bacterial mechanosensitive channels are gated directly by bilayer tension. Recent work has demonstrated that bilayer tension may also activate eukaryotic mechanosensitive channels such as TREK-1/2. Using bleb-based electrophysiology we have shown that Piezo1 can also be gated by membrane tension, supported by the fact that purified mouse Piezo1 can be gated in pure lipid systems. More recently we have explored the influence of cytoskeletal proteins on Piezo1 and how these components modulate the channels inherent tension sensitivity using patch fluorometry. Moreover, we measure the mechanical properties of the cells expressing these channels concomitantly while we estimate the membrane tension necessary for channel activation. Changes in Piezo1 sensitivity are not exclusively correlated to changes in bulk mechanical properties of the cell. In the presence of STOML3 and tropomyosin4.2 the membrane tension required to gate Piezo1 is ≤ 0.5 mN/m, which is well within a physiological range. In contrast, the activation threshold of Piezo1 in the presence of Filamin A increases. Our results shed light on the ability of different structural scaffold proteins to sensitize or desensitize Piezo1 channels to mechanical stimuli by modulating their tension sensitivity. This model holds general applicability for sensitization/desensitization of all inherently mechanosensitive ion channels by cytoskeletal elements.