Every time we feel a tap on our skin, specialized nerve cells convert that physical force into electrical signals that our brain interprets as touch. Scientists have long known that a protein called PIEZO2 acts as an important sensor of touch, but it remained unclear why PIEZO2 is specialized for the local mechanical forces experienced by sensory neurons, whereas its close relative PIEZO1 responds to broader mechanical stresses, such as those generated during cell elongation, as occurs in blood vessels.
Now, a new study from Scripps Research helps fill that gap. The survey results are nature March 4, 2026 We reveal how PIEZO2 detects certain types of force and explain why evolution may have selected PIEZO2 as a primary sensor for light body touches. This study may guide future studies of sensory disorders associated with PIEZO2 mutations.
Touch is one of our most basic senses, but how it is processed at the molecular level was not fully understood. We wanted to know how the structure of PIEZO2 actually makes cells feel. ”
Erdem Patapoutyan, Study Co-Senior Author, Neurobiology, Scripps Research Institute Presidential Endowed Chair
He is also a Howard Hughes Medical Institute Investigator.
In 2021, Patapoutian was jointly awarded 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 cells, generating electrical signals that allow us to sense touch, body position, and certain types of pain.
Although PIEZO1 and PIEZO2 appear nearly identical in molecular models, they behave quite differently in living cells. PIEZO2 is particularly important in the somatosensory nervous system, the network of neurons that detect touch. These cells are very sensitive to small indentations, such as tapping the skin. In contrast, PIEZO1 responds more readily to general membrane stretching, such as when cells are pulled or swollen, rather than poking at specific points.
To investigate this difference, the research team used Minimum Fluorescence Photon Flux (MINFLUX) super-resolution microscopy, with imaging assistance from Professor Scott Henderson, Director of the Scripps Research Core Microscopy Facility, and Senior Staff Scientist Kathryn Spencer.
While other imaging techniques, such as cryo-electron microscopy (cryo-EM), have been able to obtain detailed, static images of frozen PIEZO proteins that provide a reference for their overall shape, MINFLUX allows scientists to track the position and movement of proteins within cells with nanometer-scale precision. By the way, a nanometer is one billionth of a meter, or about one hundred thousandth the width of a human hair.
“While Cryo-EM provides beautiful structural snapshots, it cannot show 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 like about this study led by Eric Mulhall is that it ties together the findings on an unusually broad scale,” Pataptian added. “This is one of the few studies I’ve seen that connects single-molecule insights to physiological function, from nanometer-scale super-resolution microscopy to in vitro and in vivo experiments.”
Using MINFLUX and electrical recordings that measure ion flow, the team observed how PIEZO2 changes shape when force is applied. These electrical recordings were made by second author and staff scientist Oleg Yarishkin and allowed a direct relationship between structural changes in PIEZO2 and channel activity. The researchers found that PIEZO2 is inherently more rigid than PIEZO1 and is 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 help maintain the cell’s shape and transmit forces.
Tethering occurs through a protein called filamin-B, which connects membrane proteins to actin filaments. When a cell is poked, this internal link helps transmit force to PIEZO2, facilitating the opening of the channel. However, when the tether was intact, simple membrane stretching did not activate PIEZO2.
The researchers identified a specific region where PIEZO2 connects to filamin B and showed that disrupting this connection changes how the channel senses force. In mouse sensory neurons, when the neurons responsible for detecting touch removed their tethers, PIEZO2 became less sensitive to indentations, allowing the channels to respond to membrane stretching, a type of force that is normally ignored.
“I was amazed at how differently the two channels responded to the same type of force,” Mulhall recalls. “While membrane stretching dilates and activates PIEZO1, we observed the opposite response with PIEZO2, strongly indicating that these channels function through different mechanisms.”
The findings suggest that cells can fine-tune their sensitivity to contact not only by choosing which ion channels to use, but also by controlling how those channels are physically integrated within the cell. Because filamin B is widely expressed throughout tissues, tethering may help tune PIEZO2 to everyday gentle touch. Understanding this mechanism may shed light on what happens when function is impaired.
Mutations in PIEZO2 can cause sensory deficits that affect touch and body awareness, while mutations in filamin B are associated with skeletal and developmental conditions. By revealing how these proteins interact, this study provides a clearer framework for interpreting such genetic findings and guiding future research on sensory function.
“Our results have changed the perspective on how contacts begin at the molecular level,” explains Patapoutian. “The physical connections of proteins within cells determine what kinds of forces they can sense. This is a new way of thinking about how we sense the world around us.”
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Reference magazines:
Mulhall, E.M.; Others. (2026). Molecular basis of force selectivity by PIEZO2. nature. DOI: 10.1038/s41398-026-03905-x, https://www.nature.com/articles/s41586-026-10182-7.
