Understanding PIEZO2 mutations and sensory disorders

Whenever we feel a gentle tap on the skin, specialized nerve cells convert this 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 has remained unclear why PIEZO2 is specialized for localized mechanical forces experienced by sensory neurons, while its close relative PIEZO1 responds to broader mechanical stresses such as those generated when cells are stretched, 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, explain how PIEZO2 detects specific types of force and explain why evolution may have chosen 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 do not fully understand how it is processed at the molecular level. “We wanted to see how the structure of PIEZO2 shapes what a cell can sense.”

Ardem Patapoutian, Research Associate and Presidential Chair, Neurobiology, The Scripps Research Institute

He is also a Howard Hughes Medical Institute investigator.

In 2021, Patapoutian shared the Nobel Prize in Physiology or Medicine for the discovery of 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, producing electrical signals that allow us to sense touch, body position, and certain types of pain.

Although PIEZO1 and PIEZO2 look almost identical in molecular models, they behave very differently in living cells. PIEZO2 is particularly important in the somatosensory nervous system, the network of nerve cells that detects touch. These cells are very sensitive to small indentations, such as a light blow to the skin. In contrast, PIEZO1 responds more readily to general membrane stretching, such as when a cell is pulled or swollen, rather than being poked at a specific point.

To investigate the difference, the research team used a minimum fluorescence photon flux superresolution (MINFLUX) microscope, with imaging support provided by Professor Scott Henderson, who directs the Scripps Nuclear Microscopy Research Unit, and Senior Scientist Kathryn Spencer.

While other imaging techniques, including cryogenic electron microscopy (cryo-EM), have captured detailed but static PIEZO images of frozen proteins that serve as references for overall shape, MINFLUX allows scientists to track the positions and movements of proteins in cells with nanometer precision. For the environment, 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 project, 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 extends from nanoscale super-resolution microscopy 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 a force was applied. These electrical recordings, performed by second author and staff scientist Oleg Yarishkin, allowed a direct link between PIEZO2 structural changes and channel activity. The team found that PIEZO2 was intrinsically more rigid than PIEZO1 and physically linked (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 via a protein called filamin-B, which links membrane proteins to actin filaments. When a cell was hit, this internal link helped transfer force to PIEZO2, making the channel more likely to open. However, simple membrane stretch did not activate PIEZO2 when tethering was intact.

The team identified the specific region where PIEZO2 bound to filamin-B and showed that disrupting this binding changed the way the channel sensed force. In mouse sensory neurons—the nerve cells responsible for detecting touch—unbinding reduced PIEZO2’s sensitivity to indentation and unexpectedly allowed the channel to respond to membrane stretch, a type of force it normally ignores.

“We were surprised by how differently the two channels responded to the same type of force,” Mulhall recalls. “Membrane stretch stretches and activates PIEZO1, although we observed the opposite response in PIEZO2. This was a strong indication that these channels work through different mechanisms.”

The findings suggest that cells can regulate 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 in tissues, tethering may help tailor PIEZO2 to record gentle, everyday touch. Understanding this mechanism could also shed light on what happens when it is impaired.

Mutations in PIEZO2 can cause sensory disorders that affect touch and body awareness, while mutations in filamin-B are associated with skeletal and developmental disorders. 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 change the perspective on how touch starts at the molecular level,” explains Patapoutian. “The physical connections of a protein inside a cell determine what kinds of forces it can sense. This is a new way of thinking about how we sense the world around us.”