Chronic Pain Treatments Could Target Ion Channel Implicated in Touch Perception

Every hug, every handshake, every dexterous act engages and requires touch perception, and so understanding the molecular basis of touch is important. But to date, scientists had only known about one ion channel, Piezo2, that was involved in touch perception. A research team headed by Gary Lewin, PhD, head of the Molecular Physiology of Somatic Sensation Lab at the Max Delbrück Center has now discovered a second ion channel, named Elkin1, that also plays a vital role in touch perception. It is likely that the protein is directly involved in converting a mechanical stimulus, such as light touch, into an electrical signal. When Elkin1 is present, the research showed, the receptors in the skin can transmit the touch signals via nerve fibers, to the central nervous system and brain.

The team’s preclinical study, including experiments in stem-cell derived human neurons, and in live mice, also implicated Elkin1 in transmitting painful mechanical stimuli, indicating that this ion channel could feasibly represent a potential target for strategies to treat chronic pain.

Reporting on their work in Science “Touch sensation requires the mechanically gated ion channel ELIN1,” the researchers concluded, “Our data identify ELKIN1 as a core component of touch transduction in mice and potentially in humans.”

Touch sensation is “fundamental to our sense of self, our social interactions, and our exploration of the tactile world,” the authors wrote. “Sensation is initiated at specialized end organs in the skin, innervated by low-threshold mechanoreceptors (LTMRs) with their cell bodies in the dorsal root ganglia (DRGs). The peripheral endings of these LTMRs are equipped with mechanically gated ion channels that can be opened with very small forces, to start and enable touch perception.

For over 20 years Lewin has been studying the molecular basis of the sensation of touch. “Until now, we had known that the ion channel—Piezo2—is required for touch perception, but it was clear that this protein alone cannot explain the entirety of touch sensation,” Lewin explained. The newly reported work by Lewin and team has now discovered a new— and so only the second—ion channel, named Elkin1, that plays a vital role in touch perception.

In fact, Lewin’s team came across Elkin1 a few years ago while investigating a malignant melanoma cell line. The researchers had found that the protein is required for sensing mechanical forces by these highly motile cancer cells. “We previously identified ELKIN1 (TMEM87A) as a protein that is both necessary and sufficient to confer mechanosensitivity to highly metastatic human melanoma cells,” they stated. “Now we wanted to determine whether the same protein also plays a role in touch sensation,” Lewin explained.

For their study now reported in Science, the researchers carried out experiments in lab-grown cells, which provided “multiple lines of evidence that ELKIN1 is likely an ion channel  that can detect mechanical force.” They then bred genetically modified mice that lacked the Elkin1 gene (Elkin1^−/− mice) and conducted simple behavioral experiments that involved lightly brushing a cotton swab against the rodents’ hind paws. “Usually, normal mice react to the cotton swab 90% of the time,” said Lewin.

“In contrast, mice lacking Elkin1 only reacted half of the time, indicating touch insensitivity.” Importantly, the rodents’ reaction to non-mechanical stimuli like temperature was not affected. “… nonmechanosensory modalities, such as heat withdrawal thresholds, were unaltered in Elkin1^−/− mice,” the team pointed out. “Elkin1^−/− mice also showed no deficits in open-field locomotion.”

To investigate further at the neuronal level, Sampurna Chakrabarti, PhD, a scientist in Lewin’s team, used the patch clamp method to record the electrical activity of sensory neurons in response to poking the neuronal membrane.

“Around half of the neurons in genetically modified mice lacking Elkin1 didn’t respond to mechanical stimuli, and no signal transmission occurred,” says Chakrabarti. “Touch insensitivity in Elkin1^−/− mice was caused by a loss of mechanically activated currents (MA currents) in around half of all sensory neurons activated by light touch (low-threshold mechanoreceptors),” the team commented. “Reintroduction of Elkin1 into sensory neurons from Elkin1^−/− mice restored MA currents.”

Further experiments confirmed that there were no signals relayed from the neuron’s receptor ending in the skin, on the first leg of the signals journey from skin to the spinal cord and brain. The team’s Australian collaborators in the lab of Professor Mirella Dottori, PhD, in the University of Wollongong also tested whether Elkin1 in necessary for touch transduction in human sensory neurons grown in a petri dish from stem cells.

Their findings also strongly suggest that Elkin1 could play a major role in human touch perception. “The ability of induced human sensory neurons to transduce mechanical forces was severely diminished after knockdown of ELKIN1,” they noted. “Thus, ELKIN1 is an ion channel gated by mechanical force that likely has a conserved role in the transduction of light touch in mice and humans.”

Interestingly, they pointed out, the phenotype observed in sensory neurons was similar to that which followed knock down or genetic ablation of the PIEZO2 mechanosensitive ion channel. And in the induced human sensory neurons, knockdown of PIEZO2 with siRNA also decreased MA currents. “ … very few MA currents remained after the knockdown of both ELKIN1 and PIEZO2,” the team stated. “… we postulated that there may be some functional interaction between PIEZO2 and ELKIN1.”

The researchers reason that during normal signal transmission, Elkin1 and Piezo2 share roles in touch perception. “Our data support a model in which ELKIN1 and PIEZO2 channels share roles in sensory mechanotransduction in LTMRs …” they commented.

The team also found evidence that Elkin1 may play a part in the transmission of painful mechanical stimuli. “If this is confirmed to be the case, we will have not only identified a second ion channel with an indispensable role in normal touch perception, but also a new potential target for treating chronic pain,” said Lewin.