PIEZO2 detects touch because it is physically tethered to the cell's skeleton

PIEZO1 and PIEZO2 look almost identical under a microscope. Both are ion channels -- protein gates embedded in cell membranes that open when force is applied, allowing charged particles to flow in and generate electrical signals. Both were discovered by Ardem Patapoutian, who shared the 2021 Nobel Prize in Physiology or Medicine for the work. But in living cells, they behave as if they are entirely different machines.

PIEZO1 responds to general membrane stretch -- the kind of broad mechanical stress that occurs when blood flows through vessels or when cells swell. PIEZO2 responds to localized indentation -- the precise, pointed force of a fingertip pressing skin. Until now, no one could fully explain why two proteins with such similar structures have such different jobs.

A study published March 4, 2026, in Nature provides the answer: PIEZO2 is physically tethered to the cell's internal scaffolding, and that tether changes everything about what forces it can detect.

Watching a protein move in real time

Previous structural studies of PIEZO proteins used cryo-electron microscopy, which produces detailed images but only of frozen, static molecules. The Scripps Research team, led by first author Eric Mulhall and senior author Patapoutian, turned to a different technique: MINFLUX super-resolution microscopy, which can track protein positions and movements in living cells with nanometer-scale precision.

At that resolution -- roughly one-billionth of a meter -- the team could observe how PIEZO2 changed shape when force was applied to the cell. They paired these imaging experiments with electrical recordings, performed by staff scientist Oleg Yarishkin, that measured ion flow through the channels in real time. The combination linked structural changes directly to channel function.

"Cryo-EM gives us beautiful structural snapshots, but it can't show us how a protein moves in its native cellular environment," Mulhall said.

The filamin-B connection

The critical finding was that PIEZO2 is physically connected to the actin cytoskeleton -- the network of protein fibers that maintains cell shape and transmits forces internally. The link between PIEZO2 and the cytoskeleton runs through a protein called filamin-B, which acts as a molecular bridge between membrane proteins and actin filaments.

When researchers poked a cell, the cytoskeletal tether conveyed force directly to PIEZO2, making the channel more likely to open. But when the membrane was simply stretched -- pulled broadly rather than indented at a point -- PIEZO2 remained closed as long as the tether was intact.

PIEZO1 showed the opposite behavior. Membrane stretch expanded and activated it readily. The same force that opened PIEZO1 left PIEZO2 unmoved.

"We were surprised by how differently the two channels responded to the same type of force," Mulhall said. "Membrane stretch expands and activates PIEZO1, though we observed the opposite response in PIEZO2."

Cutting the tether changes the rules

The team identified the specific region of PIEZO2 that connects to filamin-B, then disrupted that connection in mouse sensory neurons -- the nerve cells responsible for detecting touch. The results were striking. Without the tether, PIEZO2 lost sensitivity to indentation and, unexpectedly, gained the ability to respond to membrane stretch. In other words, un-tethered PIEZO2 started behaving more like PIEZO1.

This result suggests that the tether does not merely enhance PIEZO2's sensitivity to touch. It fundamentally defines the channel's selectivity, filtering out one type of mechanical force while amplifying another. The same protein, in the same membrane, can function as either a touch sensor or a stretch sensor depending on its physical connections inside the cell.

Implications for sensory disorders

Mutations in PIEZO2 cause sensory disorders affecting touch perception and proprioception -- the body's sense of its own position in space. Mutations in filamin-B are associated with skeletal and developmental conditions. The new findings provide a framework for understanding how disruptions in the physical connection between these two proteins might contribute to disease.

"A protein's physical connections inside a cell determine what kinds of forces it can sense," Patapoutian said. "That's a new way of thinking about how we feel the world around us."

The study was a collaboration between researchers at Scripps Research and Oregon Health and Science University. It does not address therapeutic applications directly, but the mechanistic clarity it provides -- understanding exactly why PIEZO2 detects what it detects -- lays necessary groundwork for any future intervention targeting touch-related disorders.

The work remains in the domain of basic science. Whether the filamin-B tether can be therapeutically modulated, and what the consequences of doing so would be for patients, are questions for future research.