Mechanosensitive ion channels convert external mechanical stimuli into electrochemical signals for critical processes including touch sensation, balance, and cardiovascular regulation. The best understood mechanosensitive channel, MscL, opens a wide pore, which accounts for mechanosensitive gating due to in-plane area expansion. Eukaryotic Piezo channels have a narrow pore and therefore must capture mechanical forces to control gating in another way. We present a cryo-EM structure of mouse Piezo1 in a closed conformation at 3.7Å-resolution. The channel is a triskelion with arms consisting of repeated arrays of 4-TM structural units surrounding a pore. Its shape deforms the membrane locally into a dome. We present a hypothesis in which the membrane deformation changes upon channel opening. Quantitatively, membrane tension will alter gating energetics in proportion to the change in projected area under the dome. This mechanism can account for highly sensitive mechanical gating in the setting of a narrow, cation-selective pore.

Open and Closed Case: Voltage-dependent ion channels are gated by voltage sensors that show a switchlike response to voltage differences across the membrane. Tao et al. (p. 67 ; see the cover) used mutagenesis, electrophysiology, and x-ray crystallography to gain insight into the molecular basis of this response in voltage-dependent potassium channels. An occluded site was identified that catalyzes translation of positive charges across the membrane. The closed channel appears to be associated with a distribution of conformations, depending on the degree of hyperpolarization of the membrane, whereas the open channel appears to be associated with a specific conformation. Thus, the transition of the ion channel from open to closed occurs over a very small voltage difference.

Mechanosensitive ion channels underlie neuronal responses to physical forces in the sensation of touch, hearing, and other mechanical stimuli. The fundamental basis of force transduction in eukaryotic mechanosensitive ion channels is unknown. Are mechanical forces transmitted directly from membrane to channel as in prokaryotic mechanosensors or are they mediated through macromolecular tethers attached to the channel? Here we show in cells that the K⁺ channel TRAAK (K2P4.1) is responsive to mechanical forces similar to the ion channel Piezo1 and that mechanical activation of TRAAK can electrically counter Piezo1 activation. We then show that the biophysical origins of force transduction in TRAAK and TREK1 (K2P2.1) two-pore domain K⁺ (K2P) channels come from the lipid membrane, not from attached tethers. These findings extend the “force-from-lipid” principle established for prokaryotic mechanosensitive channels MscL and MscS to these eukaryotic mechanosensitive K⁺ channels. Significance Mechanical force opens mechanosensitive ion channels in the cellular membrane to produce electrical signals that underlie sensation of touch, hearing, and other mechanical stimuli. An unanswered question is: How are mechanical forces transmitted to eukaryotic mechanosensitive channels in the membrane? We show that two mechanosensitive ion channels in eukaryotes, TRAAK (K2P4.1) and TREK1 (K2P2.1), are directly opened by mechanical force through the lipid membrane in the absence of all other cellular components. This finding extends the “force-from-lipid” paradigm established in bacterial channels to TRAAK and TREK1, eukaryotic mechanosensors.