Piezo1 ion channels mediate the conversion of mechanical forces into electrical signals and are critical for responsiveness to touch in metazoans. The apparent mechanical sensitivity of Piezo1 varies substantially across cellular environments, stimulating methods and protocols, raising the fundamental questions of what precise physical stimulus activates the channel and how its stimulus sensitivity is regulated. Here, we measured Piezo1 currents evoked by membrane stretch in three patch configurations, while simultaneously visualizing and measuring membrane geometry. Building on this approach, we developed protocols to minimize resting membrane curvature and tension prior to probing Piezo1 activity. We find that Piezo1 responds to lateral membrane tension with exquisite sensitivity as compared to other mechanically activated channels and that resting tension can drive channel inactivation, thereby tuning overall mechanical sensitivity of Piezo1. Our results explain how Piezo1 can function efficiently and with adaptable sensitivity as a sensor of mechanical stimulation in diverse cellular contexts.
Piezo ion channels are proteins that are embedded in the cell membranes of many types of tissue, including the heart, lung, skin and kidney. These proteins are essential for many biological processes, including sensing gentle touches and ensuring that blood vessels develop properly.
When stimulated by mechanical forces, a central pore in the Piezo channel opens to allow positively charged ions to flow into the cell, which triggers electrical and chemical signaling processes inside the cell. However, it was not known exactly what type of mechanical stimulus is sensed by Piezo ion channels.
Lewis and Grandl expressed Piezo ion channels in cultured human kidney cells, and opened them by applying pressure to parts of the cell membrane inside a glass pipette. This causes a number of changes to the membrane, including to its curvature and tension, either of which could potentially open the Piezo channels. However, Lewis and Grandl were able to calculate from images of the cell membrane inside the pipette that tension is the activating stimulus.
Further experiments unexpectedly revealed that the tension that is usually present in the cell membrane is sufficient to inactivate Piezo channels and prevent them from responding to an additional mechanical stimulus. This suggests that Piezo ion channels are inherently more sensitive to tension than previously realized, which could explain why different cell types appear to have different sensitivities to pressure.
Although Lewis and Grandl have now shown that Piezo channels are activated by tension, more work is needed to investigate how the Piezo ion channel senses this force, and how this leads to the channel pore opening.