How We Feel Touch

Scientists discover that a protein called PIEZO2 controls the sensation of touch in people. But what allows touch to become painful remains a mystery. Image credit: akinshin/123RF Stock Photo.

Scientists discover that a protein called PIEZO2 controls the sensation of touch in people. But what allows touch to become painful remains a mystery. Image credit: akinshin/123RF Stock Photo.

Sensory transduction is the conversion of a sensory stimulus—a flash of light, a noise, a flavor, an odor—into an electrical signal in the brain. In humans, the molecules that facilitate this process for the senses of sight, sound, taste, and smell are well known, but those responsible for the sense of touch have remained elusive—until now.

Two research groups at the U.S. National Institutes of Health (NIH) identify mutations in a gene that makes PIEZO2, a protein that responds to mechanical force, in two patients with previously undiagnosed neuromuscular disorders. Patients with the mutations had difficulty sensing gentle touch and limb movement, but were able to sense pain, including pain resulting from pressure or pinprick.

These results parallel animal studies of mice lacking the PIEZO2 protein, and leave the identity of the molecule that makes touch become painful unknown.

The research was led by Carsten Bonnemann, at the National Institute of Neurological Disorders and Stroke, and by Alexander Chesler at the National Center for Complementary and Integrative Health, in Bethesda, US.

“It is relatively rare to see such nice agreement between [research in animals] and human studies,” writes Ardem Patapoutian, Scripps Research Institute, La Jolla, US, in an email to RELIEF. “Further analysis of these patients will in turn extend our knowledge of what PIEZO2 ion channels do,” added Patapoutian, referring to the class of proteins to which PIEZO2 belongs. Patapoutian discovered PIEZO proteins in neurons and later showed how they work in fruit flies and mice, but was not involved in the current research.

The study was published online September 21 in the New England Journal of Medicine.

A surprising discovery
The initial discovery of PIEZO2 was an important first step in identifying the molecules that convert touch and possibly pain into electrical signals in the brain. In fruit flies, PIEZO2 responds to painful touch. However, later studies in mice genetically engineered to lack PIEZO2 showed a role for the protein not in pain, but rather in sensing gentle touch and proprioception—one’s ability to detect the position and movement of the body. Whether PIEZO2 served a similar purpose in humans was unknown.

In the new study, the researchers examined two unrelated patients with unusual, yet highly similar characteristics. Both patients had difficulty moving their limbs, performing reaching tasks, and had impaired ability to detect vibration. There were no deficits in cognition, and brain imaging showed no abnormalities in the brain or spinal cord.

Surprisingly, DNA sequencing by Bonnemann’s group revealed that both patients had mutations in the same gene—the one that makes PIEZO2. The researchers suspected that the mutation eliminated or reduced the function of the protein.

According to Chesler, the discovery of the mutations by Bonnemann was quite unexpected. Indeed, at the time of the genetic testing, Bonnemann’s group did not yet know that the two patients might have an altered sense of touch. However, when Chesler described to Bonnemann the previous studies of mice lacking PIEZO2 in their first meeting, “his jaw dropped,” Chesler said. Together, Chesler and Bonnemann used the DNA sequencing to find the gene that makes PIEZO2, and then used previous information about PIEZO2 from mouse studies to learn more about its function in people.

What does PIEZO2 do?
In the two patients, the researchers found that hairless skin of the palm and fingertips had markedly decreased sensitivity to touch and vibration. On hairy skin of the forearm, sensitivity to vibration was reduced, but unlike hairless skin, gentle touch was not affected. These results are comparable to what was found in studies of mice lacking PIEZO2.

Bonnemann and colleagues expanded on previous tests in mice to include a two-point touch discrimination test, which assesses people’s ability to distinguish a one-point stimulus touching the skin from a two-point stimulus. Healthy subjects used as controls were able to do so with 100% accuracy, while patients with the mutation only showed approximately 40% accuracy—scoring no better than chance.

The researchers also tested proprioception by asking the patients to make large and small movements of the arms and legs. With smaller movements of the joints, control participants were able to detect the direction of movement with 100% accuracy, but the patients could only detect the direction of movement with 40-60% accuracy, again scoring no better than chance.

Finally, during a learned motor task (reaching a finger from the nose to a target kept at arm’s length), patients with the mutation performed similarly to controls. However, when the task was performed blindfolded, both patients were unable to control the distance and speed of their movement when nearing the target.

What about pain?
The patients’ responses to mechanical pain from pinprick and pressure (and to thermal pain from hot and cold temperatures) were similar to responses in control subjects. This finding is consistent with results from animal studies showing that PIEZO2 is not involved in sensing mechanical pain.

So is there a molecule in humans that senses painful touch?

“This is really asking the million-dollar question” Chesler says. “We have previously observed no change in mechanical pain [in genetically engineered mice lacking PIEZO2], but moving forward we need to ask, is all mechanical pain created equal? There are a lot more questions we haven’t even delved into. If there is a single [molecule for sensing mechanical] pain, there would be incredible significance in that discovery.” –Hillary Doyle

To read about the research in more detail, see the related Pain Research Forum news story here.

Hillary Doyle is a PhD candidate and science writer studying pain and analgesia at Georgia State University in Atlanta.