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Home | Pregnancy Timeline | News Alerts |News Archive Dec 10, 2014

Mechano-Gated Ion Channels in the Sensory System. Image Credit: Cell




Scientists identify principal sensor for touch

A team led by biologists at The Scripps Research Institute (TSRI) has solved a long-standing mystery in neuroscience by finding the "mechano-receptor" protein mediating the sense of touch.

By the 1980s scientists had identified the main protein photoreceptor underlying a mammal's sense of sight. Since the early 1990s they have identified smell and taste receptors. But the mechano-receptor protein for the sense of touch had been elusive.

"It works in very few specialized cells and isn't abundant in those cells, and at the start we didn't have many clues about what it would look like."

Ardem Patapoutian, PhD, TSRI, and Howard Hughes Medical Institute.

Four years ago, with the help of techniques in advanced genomics, professor Ardem Patapoutian of TSRI and investigator with Howard Hughes Medical Institute, identified in mouse cells two ion-channel proteins — Piezo1 and Piezo2.

These ion-channel proteins are made mechanically active by physical force. A force strong enough to distort the cell membrane in which one of the ion channels is embedded. This pressure on the cell wall effectively switches the ion-channel from closed to open.

When the ion-channel is open, sodium and other positively charged electrolytes can flow into a cell. In a sensory nerve cell, this transit would trigger an electrical nerve impulse — thus physical force becomes translated into a neural signal.

Mice without the Piezo2 ion-channel protein in skin cells and nerve endings, lose nearly all their sensitivity to ordinary light touch, but retain an almost normal sensitivity to painful, mechanical stimuli.

"We can say with certainty that Piezo2 is the principal touch sensor in mammals."

Ardem Patapoutian, PhD

The discovery is published in the December 4, 2014 issue of Nature.

Of the two ion-channel proteins, only Piezo2 was found to be significant in touch-sensing neurons in the dorsal root ganglia of the spine that extend their nerve processes into the skin. This information led Patapoutian to focus on Piezo2 as the transducer for the sense of touch.

The Dorsal Root Ganglia

In 2013, Patapoutian had reported that Piezo2 works as the touch sensor in Merkel cells — specialized cells located in touch-sensitive nerve terminals in the skin of mice. Nerve terminals are often shaped to detect specific types and directions of force. Terminals attached to force-responsive Merkel cells or hair follicles, become even more sensitive.

The scientists had bred a special mouse for their 2013 experiments which linked Piezo2 to a fluorescent protein. The flourescent protein allowed them to verify that Piezo2 is produced in a broad range of "low-threshold mechano-receptor" nerve terminals in both hairy and hairless areas of mouse skin. Their next step was to delete the Piezo2 gene and observe whether mice still responded normally to touch. But all mice without Piezo2 died at birth. Sanjeev S. Ranade, lead author of the most recent paper, then developed a "conditional knockout" mouse in which Piezo2 was almost deleted, but only from the dorsal root ganglia neurons and Merkel cells. Electrical tests verfied that these neurons had lost virtually all their sense of ordinary light touch. "Across a range of tests, we observed a dramatic reduction in their responsiveness to ordinary light touch," added Sanjeev S. Ranade.

However, these touch-insensitive mice remained responsive to painful skin-stimuli such as heat, cold and — pinching. Painful mechanical sensations such as pinching were previously thought to require more force to activate. "But the functions of these high-threshold mechano-receptor nerves seemed unaffected in the Piezo2 knockout mice," added Patapoutian.

Patapoutian now plans to investigate how much "crosstalk" exists between these two — low-threshold and high-threshold — mechano-sensitive nerve systems. As chronic pain conditions can make even light touch feel painful, Patapoutian and colleagues want to investigate the role of Piezo2 in other parts of the body where it is also found, such as in the lungs. "This discovery now allows us to test the relationship between touch and pain." adds Patapoutian.

The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals1. It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive2. Piezo2 is a rapidly adapting, mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors known as Merkel-cell–neurite complexes3, 4. It has been demonstrated that Merkel cells have a role in vertebrate mechanosensation using Piezo2, particularly in shaping the type of current sent by the innervating sensory neuron4, 5, 6; however, major aspects of touch sensation remain intact without Merkel cell activity4, 7. Here we show that mice lacking Piezo2 in both adult sensory neurons and Merkel cells exhibit a profound loss of touch sensation. We precisely localize Piezo2 to the peripheral endings of a broad range of low-threshold mechanoreceptors that innervate both hairy and glabrous skin. Most rapidly adapting, mechanically activated currents in dorsal root ganglion neuronal cultures are absent in Piezo2 conditional knockout mice, and ex vivo skin nerve preparation studies show that the mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2. This cellular phenotype correlates with an unprecedented behavioural phenotype: an almost complete deficit in light-touch sensation in multiple behavioural assays, without affecting other somatosensory functions. Our results highlight that a single ion channel that displays rapidly adapting, mechanically activated currents in vitro is responsible for the mechanosensitivity of most low-threshold mechanoreceptor subtypes involved in innocuous touch sensation. Notably, we find that touch and pain sensation are separable, suggesting that as-yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation.

Other contributors to the paper, "Piezo2 is the major transducer of mechanical forces for touch sensation in mice," were Seung-Hyun Woo, Adrienne E. Dubin, Bertrand Coste, Allain G. Francisco and Kritika Reddy, all from TSRI during the study; Rabih A. Moshourab, Christiane Wetzel and Valérie Bégay, of the Max-Delbrück Center for Molecular Medicine; Zhaozhu Qiu, Matt Petrus, Jayanti Mathur, James Mainquist and A.J. Wilson of the Genomics Institute of the Novartis Research Foundation, San Diego, California; and John N. Wood of University College, London.

Funding for the research came partly from the National Institutes of Health (R01 DE022358).

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