Understanding PIEZO2 mutations and sensory disorders

Every time we feel a gentle tap on the skin, specialized nerve cells convert that physical force into an electrical signal that the brain can interpret as touch. While scientists have long known that a protein called PIEZO2 acts as a key sensor for touch, it remained unclear why PIEZO2 is specialized for the localized mechanical forces experienced by sensory neurons, whereas its close relative PIEZO1 responds to broader mechanical stresses such as those generated when cells stretch, as occurs in blood vessels.

Now, a new study from Scripps Research helps fill that gap. The findings, published in Nature on March 4, 2026, clarify how PIEZO2 detects specific types of force and explain why evolution may have selected it as the body's primary sensor for light touch. This work may guide future exploration into sensory disorders linked to PIEZO2 mutations.

Touch is one of our most fundamental senses, yet we didn't fully understand how it's processed at the molecular level. We wanted to see how the structure of PIEZO2 shapes what a cell can actually feel."

Ardem Patapoutian, Study Co-Senior Author and Presidential Endowed Chair, Neurobiology, Scripps Research Institute

He is also a Howard Hughes Medical Institute Investigator.

In 2021, Patapoutian shared the Nobel Prize in Physiology or Medicine for discovering PIEZO1 and PIEZO2: ion channels, or protein "gates," embedded in cell membranes that open in response to force. When these gates open, charged particles flow into the cell, generating electrical signals that allow us to feel touch, body position and certain types of pain.

Although PIEZO1 and PIEZO2 appear nearly identical in molecular models, they behave very differently in living cells. PIEZO2 is especially important in the somatosensory nervous system, the network of nerve cells that detects touch. These cells are highly sensitive to small indentations, like a light tap on the skin. By contrast, PIEZO1 responds more readily to general membrane stretch, such as when a cell is pulled or swollen, rather than poked at a specific point.

To investigate the difference, the research team used minimal fluorescence photon flux (MINFLUX) super-resolution microscopy, with imaging support provided by Professor Scott Henderson, who directs the Scripps Research Core Microscopy Facility, and Senior Staff Scientist Kathryn Spencer.

Whereas other imaging techniques, including cryogenic electron microscopy (cryo-EM), have captured detailed but static images of frozen PIEZO proteins that serve as references for overall shape, MINFLUX allows scientists to track the positions and movements of proteins in cells with nanometer-scale precision. For context, a nanometer is one-billionth of a meter-about 100,000 times smaller than the width of a human hair.

"Cryo-EM gives us beautiful structural snapshots, but it can't show us how a protein moves in its native cellular environment," notes first and co-senior author Eric Mulhall, a postdoctoral fellow in Patapoutian's lab.

"What I love about this work, led by Eric Mulhall, is that it connects discoveries across an unusually wide range of scales," adds Patapoutian. "It's one of the few studies I've seen that spans from nanometer-scale super-resolution microscopy all the way to ex vivo and in vivo experiments, linking single-molecule insights to physiological function."

Using MINFLUX along with electrical recordings that measure ion flow, the team observed how PIEZO2 changed shape when force was applied. Those electrical recordings, carried out by second author and Staff Scientist Oleg Yarishkin, allowed a direct connection between PIEZO2's structural changes and channel activity. The team found that PIEZO2 was intrinsically stiffer than PIEZO1 and physically connected (or "tethered") to the cell's internal scaffolding, known as the actin cytoskeleton. The cytoskeleton is a network of protein fibers called actin filaments that helps maintain cell shape and transmit forces.

Tethering occurs through a protein called filamin-B, which connects membrane proteins to actin filaments. When a cell was poked, this internal link helped convey force to PIEZO2, making the channel more likely to open. However, simple membrane stretching didn't activate PIEZO2 when the tether was intact.

The team identified the specific region where PIEZO2 connected to filamin-B and showed that disrupting this connection changed how the channel sensed force. In mouse sensory neurons-the nerve cells responsible for detecting touch-removing the tether reduced PIEZO2's sensitivity to indentation and unexpectedly allowed the channel to respond to membrane stretch, a type of force it would normally ignore.

"We were surprised by how differently the two channels responded to the same type of force," recalls Mulhall. "Membrane stretch expands and activates PIEZO1, though we observed the opposite response in PIEZO2. This was a strong indication that these channels operate through distinct mechanisms."

The findings suggest that cells can fine-tune their sensitivity to touch not only by choosing which ion channel to use, but also by controlling how that channel is physically integrated within a cell. Because filamin-B is widely expressed across tissues, tethering may help tailor PIEZO2 for registering gentle, everyday touch. Understanding this mechanism could also shed light on what happens when it's impaired.

Mutations in PIEZO2 can cause sensory disorders affecting touch and body awareness, while mutations in filamin-B are associated with skeletal and developmental conditions. By clarifying how these proteins interact, the study provides a clearer framework for interpreting such genetic findings and guiding future research into sensory function.

"Our results shift the perspective on how touch begins at the molecular level," explains Patapoutian. "A protein's physical connections inside a cell determine what kinds of forces it can sense. That's a new way of thinking about how we feel the world around us."