A Membrane Thickness Sensor in TREK-1 Channels Transduces Mechanical Force

Abstract

The transduction of force to a biological signal is critical to all living organisms and cells. Mechanosensitive ion channels participate, but the biophysical mechanism that transduces force remains unclear. Here we show that the sensing of membrane thinning through a helix tilt in TREK-1 channels transduces force. Reconstituted TREK-1 in PC lipids with a hydrophobic thickness of ~29 Å (18:1 PC) robustly activated the channel; however, decreasing the thickness to ~26 Å (16:1 PC) or increasing to ~36 Å (22:1 PC) inhibited the channel. Increasing bilayer thickness by adding cholesterol (10-40%), or thinning the membrane with stretch, polyunsaturated fatty acids, or heat shifted the thickness dependence. The thickness sensitivity was located near a lipid-binding motif on a known gating helix at the end of the fourth transmembrane domain. We propose a stretch-activation model for TREK-1 where tension causes membrane thinning and TREK-1 senses membrane thinning to transduce the signal.