A team from The Scripps Research Institute (TSRI) in La Jolla, California, has just published a very important finding for sensory physiology research. Professor Ardem Patapoutian and his collaborators have identified the mechanoreceptor protein that mediates the sense of touch in mammals: the Piezo2 ion-channel protein of the Merkel cell-neurite complex.

Merkel cells are receptor cells found in the skin of vertebrates, in the inner layer of the epidermis. They are associated with the sense of light touch discrimination of fine details of objects. Merkel cells have synaptic contacts with sensory afferent neurons, forming a complex with sensory nerve endings – the aforementioned Merkel cell-neurite complex. This complex mediates different aspects of touch responses. Its presence in the skin has been known for decades, but the specific function of each cell type has remained unknown.

Recent studies have finally shed light on this mystery. Merkel cells were shown to have the ability to encode mechanical inputs and this provided an important clue to understanding how the skin communicates with neurons.

A great advance into understanding the detailed mechanism of this process was made four years ago, when Patapoutian and colleagues identified the proteins Piezo1 and Piezo2 as components of mechanically-activated cation channels and showed that the elimination of Piezo2 from sensory neurons could reduce mechanical activation. This was a clear indication that Piezo2 could have a fundamental role in touch processing.

Earlier this year, Patapoutian’s team published an article where they showed that Piezo2 was expressed in Merkel cells and that these could produce touch-sensitive currents in vitro. They showed that Merkel cell mechanosensitivity completely depended on Piezo2.  Their results indicated that Piezo2 could be the paramount channel for Merkel cell mechanotransduction and presented the Piezos as potential key players in the physiology of mechanical sensation in mammals.

Another important outcome of this study was the view that both Merkel cells and sensory afferents could act jointly as mechanosensors. They hypothesized that this two-receptor system could act as a fine-tuning mechanism to achieve highly detailed perception of objects and textures.

In their latest study, recently published in Nature, they extended their research to the touch-sensitive nerve terminals themselves. Their study demonstrated that Piezo2 could be found in the peripheral nerve endings of a broad range of sensory neurons innervating the skin, and that the mechanosensitivity of these neurons strongly depended on Piezo2. They also showed that the absence of Piezo2 in sensory neurons led to a marked loss of touch sensation. Importantly, they saw that the almost complete deficit in light-touch sensation did not affect other sensory functions. This allowed them to conclude that Piezo2 is responsible for the mechanical sensitivity of most low-threshold mechanoreceptor subtypes involved in innocuous touch sensation.

The importance of these findings extends beyond the understanding of touch physiology. By determining that Piezo2’s function is specific for touch, they showed that touch and pain sensations are physiologically separable. This put forward the hypothesis that painful mechanosensation may also rely on the activation of a specific ion channel that remains to be identified. Also, it is well known that sensitization associated with chronic pain can make even light touch feel painful.

These findings open the door for research on how the mechanisms of sensitization may alter touch physiology and turn touch into a painful stimulus.

References

Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, & Patapoutian A (2010). Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science (New York, N.Y.), 330 (6000), 55-60 PMID: 20813920

Coste B, Xiao B, Santos JS, Syeda R, Grandl J, Spencer KS, Kim SE, Schmidt M, Mathur J, Dubin AE, Montal M, & Patapoutian A (2012). Piezo proteins are pore-forming subunits of mechanically activated channels. Nature, 483 (7388), 176-81 PMID: 22343900

Maksimovic S, Nakatani M, Baba Y, Nelson AM, Marshall KL, Wellnitz SA, Firozi P, Woo SH, Ranade S, Patapoutian A, & Lumpkin EA (2014). Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors. Nature, 509 (7502), 617-21 PMID: 24717432

Ranade SS, Woo SH, Dubin AE, Moshourab RA, Wetzel C, Petrus M, Mathur J, Bégay V, Coste B, Mainquist J, Wilson AJ, Francisco AG, Reddy K, Qiu Z, Wood JN, Lewin GR, & Patapoutian A (2014). Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature, 516 (7529), 121-5 PMID: 25471886

Woo SH, Lumpkin EA, & Patapoutian A (2014). Merkel cells and neurons keep in touch. Trends in cell biology PMID: 25480024

Woo SH, Ranade S, Weyer AD, Dubin AE, Baba Y, Qiu Z, Petrus M, Miyamoto T, Reddy K, Lumpkin EA, Stucky CL, & Patapoutian A (2014). Piezo2 is required for Merkel-cell mechanotransduction. Nature, 509 (7502), 622-6 PMID: 24717433

Image via Luisma Tapia / Shutterstock.