A new clue to how the skin detects physical touch

Amazing stuff!

"... 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  ... 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. ...

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 ... 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. ..."

From the abstract:

"PIEZOs are mechanically gated ion channels that transduce force into electrochemical signals.
PIEZO1 responds to diverse stimuli including membrane stretch2 and shear stress, whereas 

PIEZO2 is generally tuned to detect cellular indentation. The functional specialization of PIEZO2 is proposed to underlie its distinct physiological roles, including mediating the sense of touch. How PIEZO2 achieves this selectivity despite its close structural similarity to PIEZO1 is unclear.
Here we combine single-molecule MINFLUX fluorescence nanoscopy with electrophysiology to link the conformational states of PIEZO2 to channel gating in intact cells. We find that PIEZO2 is intrinsically more rigid than PIEZO1, and that disparate mechanical stimuli paradoxically evoke opposite conformational and gating responses in each channel.

These unique gating properties arise in part from a connection to the actin cytoskeleton, and we identify filamin-B (FLNB) as a molecular tether that is required for this interaction. This complex alters how force is transmitted to PIEZO2 and confers heightened sensitivity to and selectivity for cellular indentation. PIEZO2 and FLNB are co-expressed in somatosensory neurons and colocalize within tens of nanometres at the end organs of cutaneous mechanosensory afferents. These findings help to explain why PIEZO2 is a specialized mechanosensor and provide a molecular blueprint for understanding how cells decode diverse mechanical stimuli across tissues and organ systems."

A new clue to how the body detects physical force | Scripps Research

The molecular basis of force selectivity by PIEZO2 (open access)

Fig. 1: The divergent structural mechanics of PIEZO1 and PIEZO2 in a cell membrane.