Piezo2 tension sensitivity and its modulation by alternative splicing

bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-17

Piezo2 is a force-gated ion channel that functions as a sensor of mechanical touch, proprioception, lung inflation, and gut transit. Human Piezo2 contains seven domains that are alternatively spliced in a tissue-specific fashion resulting in the expression of at least 22 distinct variants. Despite the relevance of Piezo2 in human physiology, its sensitivity to membrane tension, and how this fundamental biophysical property is affected by alternative splicing, are unknown. Here, we use cell-attached pressure-clamp electrophysiology combined with differential interference contrast microscopy to quantify the response of Piezo2 to membrane tension and identify the alternatively spliced exon 35 as a domain sufficient to confer high sensitivity to membrane tension and cellular indentation. We further show that physiological variants of Piezo2 sense mechanical forces with distinct sensitivities and dynamic ranges. Together, our findings rationalize how Piezo2 variants may fulfill distinct physiological functions required for somatosensation and interoception.

BPS2025 - Piezo1 ion channels are capable of conformational signaling

Biophysical Journal · 2025-02-01

BPS2025 - Piezo1 ion channels are capable of conformational signaling

Biophysical Journal · 2025-02-01

BPS2025 - A closed-loop system for millisecond readout and control of membrane tension

Biophysical Journal · 2025-02-01 · 1 citations

A closed-loop system for millisecond readout and control of membrane tension

Biophysical Journal · 2025-04-01 · 2 citations

Piezo1 ion channels are capable of conformational signaling

bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-29 · 1 citations

Piezo1 is a mechanically activated ion channel that senses forces with short latency and high sensitivity. Piezos undergo large conformational changes, induce far-reaching deformation onto the membrane, and modulate the function of two-pore potassium (K2P) channels. Taken together, this led us to hypothesize that Piezos may be able to signal their conformational state to other nearby proteins. Here, we use chemical control to acutely restrict Piezo1 conformational flexibility and show that Piezo1 conformational changes, but not ion permeation through it, are required for modulating the K2P channel TREK1. Super-resolution imaging and stochastic simulations further reveal that both channels do not co-localize, which implies that modulation is not mediated through direct binding interactions; however, at high Piezo1 densities, most TREK1 channels are within the predicted Piezo1 membrane footprint, suggesting the footprint may underlie conformational signaling. We speculate that physiological roles originally attributed to Piezo1 ionotropic function could, alternatively, involve conformational signaling.

Piezo1 ion channels are capable of conformational signaling

Neuron · 2024-07-22 · 25 citations

Subconductance states add complexity to Piezo1 gating model

Trends in Biochemical Sciences · 2024-05-29 · 1 citations

The energetics of rapid cellular mechanotransduction

Proceedings of the National Academy of Sciences · 2023-02-16 · 14 citations

Cells throughout the human body detect mechanical forces. While it is known that the rapid (millisecond) detection of mechanical forces is mediated by force-gated ion channels, a detailed quantitative understanding of cells as sensors of mechanical energy is still lacking. Here, we combine atomic force microscopy with patch-clamp electrophysiology to determine the physical limits of cells expressing the force-gated ion channels (FGICs) Piezo1, Piezo2, TREK1, and TRAAK. We find that, depending on the ion channel expressed, cells can function either as proportional or nonlinear transducers of mechanical energy and detect mechanical energies as little as ~100 fJ, with a resolution of up to ~1 fJ. These specific energetic values depend on cell size, channel density, and cytoskeletal architecture. We also make the surprising discovery that cells can transduce forces either nearly instantaneously (<1 ms) or with a substantial time delay (~10 ms). Using a chimeric experimental approach and simulations, we show how such delays can emerge from channel-intrinsic properties and the slow diffusion of tension in the membrane. Overall, our experiments reveal the capabilities and limits of cellular mechanosensing and provide insights into molecular mechanisms that different cell types may employ to specialize for their distinct physiological roles.

The energetics of rapid cellular mechanotransduction

Biophysical Journal · 2023-02-01 · 2 citations