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Research illuminates ‘touchy’ subject

By solving a long standing scientific mystery, the common saying “you just hit a nerve” might need to be updated to “you just hit a Merkel cell,” jokes Jianguo Gu, PhD, a pain researcher at the University of Cincinnati (UC).

That’s because Gu and his research colleagues have proved that Merkel cells— which contact many sensory nerve endings in the skin—are the initial sites for sensing touch.

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"Scientists have spent over a century trying to understand the function of this specialized skin cell and now we are the first to know … we’ve proved the Merkel cell to be a primary point of tactile detection," Gu, principal investigator and a professor in UC’s department of anesthesiology, says of their research study published in the April 15 edition of Cell, a leading scientific journal.

Of all the five senses, touch, Gu says, has been the least understood by science—especially in relation to the Merkel cell, discovered by Friedrich Sigmund Merkel in 1875.

"It’s been a great debate because for over two centuries nobody really knew what function this cell had," Gu says, adding that while some scientists—including him—suspected that the Merkel cell was related to touch because of the high abundance of these cells in the ridges of fingertips, the lips and other touch sensitive spots throughout the body; others dismissed the cell as not related to sensing touch at all.

To prove their hypothesis that Merkel cells were indeed the very foundation of touch, Gu’s team—which included UC postgraduate fellow Ryo Ikeda, PhD—studied Merkel cells in rat whisker hair follicles , because the hair follicles are functionally similar to human fingertips and have high abundance of Merkel cells. What they found was that the cells immediately fired up in response to gentle touch of whiskers.

"There was a marked response in Merkel cells; the recording trace ‘spiked’. With non-Merkel cells you don’t get anything," says Ikeda.

What they also found, and of equal importance, both say, was that gentle touch makes Merkel cells to fire “action potentials” and this mechano-electrical transduction was through a receptor/ion channel called the Piezo2.

"The implications here are profound," Gu says, pointing to the clinical applications of treating and preventing disease states that affect touch such as diabetes and fibromyalgia and pathological conditions such as peripheral neuropathy. Abnormal touch sensation, he says, can also be a side effect of many medical treatments such as with chemotherapy.

The discovery also has relevance to those who are blind and rely on touch to navigate a sighted world.

"This is a paradigm shift in the entire field," Gu says, pointing to touch as also indispensable for environmental exploration, tactile discrimination and other tasks in life such as modern social interaction.

"Think of the cellphone. You can hardly fit into social life without good touch sensation."

(Source: eurekalert.org)

Filed under sense of touch touch merkel cells ion channels Piezo2 neuroscience science

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Scientists Provide New Grasp of Soft Touch A study led by scientists at The Scripps Research Institute (TSRI) has helped solve a long-standing mystery about the sense of touch. The “gentle touch” sensations that convey the stroke of a finger, the fine texture of something grasped and the light pressure of a breeze on the skin are brought to us by nerves that often terminate against special skin cells called Merkel cells. These skin cells’ role in touch sensation has long been debated in the scientific community. The new study, however, suggests a dual-sensor system involving the Merkel cell and an associated nerve end in touch sensation. “In this long debate over the role of Merkel cells, it appears that both camps were right,” said the study’s senior author Ardem Patapoutian, a Howard Hughes Medical Institute (HHMI) Investigator and professor at TSRI’s Dorris Neuroscience Center and Department of Molecular & Cellular Neuroscience. “The nerve ends respond to touch, but so do the adjacent Merkel cells.” The report appears in an Advance Online Publication of Nature on April 6, 2014. In addition to elucidating the mammalian sense of touch, whose mechanisms until recently have been obscure, the findings could have relevance for certain pain syndromes in which touch sensations trigger pain—even the light pressure of a shirt on the skin or a breeze against the skin. “Touch and pain are very closely related,” said Patapoutian, “and thus the characterization of these mechanisms of touch should help us to understand pain better too.” Opening the Flow The discovery comes four years after the Patapoutian laboratory identified a protein called Piezo2 as a mechanically activated “ion channel” protein with a likely role in touch sensation. Ion channels are embedded in the outer membranes of various cell types and nerve fibers throughout the body. Piezo2 ion channels have been thought to respond to the stretching of the nerve membrane where they are embedded—a stretching caused by something that presses against the skin, for example. When activated in this way, the ion channels open to allow an inflow of sodium or other positively charged ions. Such a surge of electrical charge into a nerve can initiate a signal that travels up the nerve and to the brain via a relay of neurons along the spine. In the earlier study, Patapoutian’s team found evidence that Piezo2 proteins are made within touch-sensing neurons, including gentle-touch neurons that extend their nerves into the skin and against the mysterious Merkel cells. In the new study, Patapoutian and his colleagues set out to learn more. In Pursuit of Answers The team began by creating a line of mice in which the activity of the Piezo2 gene also causes the production of a fluorescing protein called GFP. Guided by these fluorescent beacons as well as other markers, they found a high concentration of Piezo2 in Merkel cells in the skin of the mice. “You can easily miss Piezo2 expression in the skin, because it’s not highly expressed there, aside from the tiny population of Merkel cells,” said first author Seung-Hyun Woo, a postdoctoral fellow in the Patapoutian laboratory. Next the researchers sought proof of Piezo2’s role in Merkel cells, essentially by subtracting the protein from those cells and observing the result. To do this—a particularly challenging feat—they created a new line of mice in which the Piezo2 gene is specifically “knocked out” of all skin cells, including Merkel cells, but left intact everywhere else where it is ordinarily produced. Piezo2 skin-knockout mice and their Merkel cells appeared normal. The mice also responded normally on most standard tests of touch and pain sensitivity. But on the so-called von Frey test, in which thin, bendable fibers are pressed against the mice’s paws with varying force, the effect of the loss of Piezo2 became apparent. “The mice whose Merkel cells lacked Piezo2 didn’t respond to the gentler forces as much as the control mice did,” said Woo. Examining this change in responsiveness in more detail, Woo and her colleagues isolated Merkel cells from the two groups of mice. They found that those Merkel cells lacking Piezo2 failed to show the usual current flows when gently pushed with a probe. Collaborating researchers in the laboratory of Cheryl L. Stucky at the Medical College of Wisconsin showed that gentle touch-sensing nerves known as slowly adapting (SA) Aβ fibers generally responded with a lower frequency of signaling in the mice lacking Piezo2 in Merkel cells. Another collaborating laboratory, led by Ellen A. Lumpkin at Columbia University, showed that Merkel cell-associated nerves also responded less durably to test stimuli on skin in these same mice. “It all shows that the Merkel cells play an important role in touch sensing and that they need Piezo2 to do so,” Woo said. The findings were bolstered by a separate study from Lumpkin’s laboratory—of which Patapoutian is a co-author—that is reported in the same issue of Nature. In that study, mice engineered to lack Merkel cells exhibited touch-sensing deficits very similar to those described in the Patapoutian group’s study. (Image: iStockphoto)

Scientists Provide New Grasp of Soft Touch

A study led by scientists at The Scripps Research Institute (TSRI) has helped solve a long-standing mystery about the sense of touch.

The “gentle touch” sensations that convey the stroke of a finger, the fine texture of something grasped and the light pressure of a breeze on the skin are brought to us by nerves that often terminate against special skin cells called Merkel cells. These skin cells’ role in touch sensation has long been debated in the scientific community. The new study, however, suggests a dual-sensor system involving the Merkel cell and an associated nerve end in touch sensation.

“In this long debate over the role of Merkel cells, it appears that both camps were right,” said the study’s senior author Ardem Patapoutian, a Howard Hughes Medical Institute (HHMI) Investigator and professor at TSRI’s Dorris Neuroscience Center and Department of Molecular & Cellular Neuroscience. “The nerve ends respond to touch, but so do the adjacent Merkel cells.”

The report appears in an Advance Online Publication of Nature on April 6, 2014.

In addition to elucidating the mammalian sense of touch, whose mechanisms until recently have been obscure, the findings could have relevance for certain pain syndromes in which touch sensations trigger pain—even the light pressure of a shirt on the skin or a breeze against the skin.

“Touch and pain are very closely related,” said Patapoutian, “and thus the characterization of these mechanisms of touch should help us to understand pain better too.”

Opening the Flow

The discovery comes four years after the Patapoutian laboratory identified a protein called Piezo2 as a mechanically activated “ion channel” protein with a likely role in touch sensation.

Ion channels are embedded in the outer membranes of various cell types and nerve fibers throughout the body. Piezo2 ion channels have been thought to respond to the stretching of the nerve membrane where they are embedded—a stretching caused by something that presses against the skin, for example.

When activated in this way, the ion channels open to allow an inflow of sodium or other positively charged ions. Such a surge of electrical charge into a nerve can initiate a signal that travels up the nerve and to the brain via a relay of neurons along the spine.

In the earlier study, Patapoutian’s team found evidence that Piezo2 proteins are made within touch-sensing neurons, including gentle-touch neurons that extend their nerves into the skin and against the mysterious Merkel cells.

In the new study, Patapoutian and his colleagues set out to learn more.

In Pursuit of Answers

The team began by creating a line of mice in which the activity of the Piezo2 gene also causes the production of a fluorescing protein called GFP. Guided by these fluorescent beacons as well as other markers, they found a high concentration of Piezo2 in Merkel cells in the skin of the mice.

“You can easily miss Piezo2 expression in the skin, because it’s not highly expressed there, aside from the tiny population of Merkel cells,” said first author Seung-Hyun Woo, a postdoctoral fellow in the Patapoutian laboratory.

Next the researchers sought proof of Piezo2’s role in Merkel cells, essentially by subtracting the protein from those cells and observing the result. To do this—a particularly challenging feat—they created a new line of mice in which the Piezo2 gene is specifically “knocked out” of all skin cells, including Merkel cells, but left intact everywhere else where it is ordinarily produced.

Piezo2 skin-knockout mice and their Merkel cells appeared normal. The mice also responded normally on most standard tests of touch and pain sensitivity. But on the so-called von Frey test, in which thin, bendable fibers are pressed against the mice’s paws with varying force, the effect of the loss of Piezo2 became apparent. “The mice whose Merkel cells lacked Piezo2 didn’t respond to the gentler forces as much as the control mice did,” said Woo.

Examining this change in responsiveness in more detail, Woo and her colleagues isolated Merkel cells from the two groups of mice. They found that those Merkel cells lacking Piezo2 failed to show the usual current flows when gently pushed with a probe.

Collaborating researchers in the laboratory of Cheryl L. Stucky at the Medical College of Wisconsin showed that gentle touch-sensing nerves known as slowly adapting (SA) Aβ fibers generally responded with a lower frequency of signaling in the mice lacking Piezo2 in Merkel cells. Another collaborating laboratory, led by Ellen A. Lumpkin at Columbia University, showed that Merkel cell-associated nerves also responded less durably to test stimuli on skin in these same mice.

“It all shows that the Merkel cells play an important role in touch sensing and that they need Piezo2 to do so,” Woo said.

The findings were bolstered by a separate study from Lumpkin’s laboratory—of which Patapoutian is a co-author—that is reported in the same issue of Nature. In that study, mice engineered to lack Merkel cells exhibited touch-sensing deficits very similar to those described in the Patapoutian group’s study.

(Image: iStockphoto)

Filed under sense of touch merkel cells ion channels Piezo2 touch neuroscience science

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Scientists Identify Key Cells in Touch Sensation In a study published online today in the journal Nature, a team of Columbia University Medical Center researchers led by Ellen Lumpkin, PhD, associate professor of somatosensory biology, solve an age-old mystery of touch: how cells just beneath the skin surface enable us to feel fine details and textures. Touch is the last frontier of sensory neuroscience. The cells and molecules that initiate vision—rod and cone cells and light-sensitive receptors—have been known since the early 20th century, and the senses of smell, taste, and hearing are increasingly understood. But almost nothing is known about the cells and molecules responsible for initiating our sense of touch. This study is the first to use optogenetics—a new method that uses light as a signaling system to turn neurons on and off on demand—on skin cells to determine how they function and communicate. The team showed that skin cells called Merkel cells can sense touch and that they work virtually hand in glove with the skin’s neurons to create what we perceive as fine details and textures. “These experiments are the first direct proof that Merkel cells can encode touch into neural signals that transmit information to the brain about the objects in the world around us,” Dr. Lumpkin said. The findings not only describe a key advance in our understanding of touch sensation, but may stimulate research into loss of sensitive-touch perception. Several conditions—including diabetes and some cancer chemotherapy treatments, as well as normal aging—are known to reduce sensitive touch. Merkel cells begin to disappear in one’s early 20s, at the same time that tactile acuity starts to decline. “No one has tested whether the loss of Merkel cells causes loss of function with aging—it could be a coincidence—but it’s a question we’re interested in pursuing,” Dr. Lumpkin said. In the future, these findings could inform the design of new “smart” prosthetics that restore touch sensation to limb amputees, as well as introduce new targets for treating skin diseases such as chronic itch. The study was published in conjunction with a second study by the team done in collaboration with the Scripps Research Institute. The companion study identifies a touch-activated molecule in skin cells, a gene called Piezo2, whose discovery has the potential to significantly advance the field of touch perception. “The new findings should open up the field of skin biology and reveal how sensations are initiated,” Dr. Lumpkin said. Other types of skin cells may also play a role in sensations of touch, as well as less pleasurable skin sensations, such as itch. The same optogenetics techniques that Dr. Lumpkin’s team applied to Merkel cells can now be applied to other skin cells to answer these questions. “It’s an exciting time in our field because there are still big questions to answer, and the tools of modern neuroscience give us a way to tackle them,” she said.

Scientists Identify Key Cells in Touch Sensation

In a study published online today in the journal Nature, a team of Columbia University Medical Center researchers led by Ellen Lumpkin, PhD, associate professor of somatosensory biology, solve an age-old mystery of touch: how cells just beneath the skin surface enable us to feel fine details and textures.

Touch is the last frontier of sensory neuroscience. The cells and molecules that initiate vision—rod and cone cells and light-sensitive receptors—have been known since the early 20th century, and the senses of smell, taste, and hearing are increasingly understood. But almost nothing is known about the cells and molecules responsible for initiating our sense of touch.

This study is the first to use optogenetics—a new method that uses light as a signaling system to turn neurons on and off on demand—on skin cells to determine how they function and communicate.

The team showed that skin cells called Merkel cells can sense touch and that they work virtually hand in glove with the skin’s neurons to create what we perceive as fine details and textures.

“These experiments are the first direct proof that Merkel cells can encode touch into neural signals that transmit information to the brain about the objects in the world around us,” Dr. Lumpkin said.

The findings not only describe a key advance in our understanding of touch sensation, but may stimulate research into loss of sensitive-touch perception.

Several conditions—including diabetes and some cancer chemotherapy treatments, as well as normal aging—are known to reduce sensitive touch. Merkel cells begin to disappear in one’s early 20s, at the same time that tactile acuity starts to decline. “No one has tested whether the loss of Merkel cells causes loss of function with aging—it could be a coincidence—but it’s a question we’re interested in pursuing,” Dr. Lumpkin said.

In the future, these findings could inform the design of new “smart” prosthetics that restore touch sensation to limb amputees, as well as introduce new targets for treating skin diseases such as chronic itch.

The study was published in conjunction with a second study by the team done in collaboration with the Scripps Research Institute. The companion study identifies a touch-activated molecule in skin cells, a gene called Piezo2, whose discovery has the potential to significantly advance the field of touch perception.

“The new findings should open up the field of skin biology and reveal how sensations are initiated,” Dr. Lumpkin said. Other types of skin cells may also play a role in sensations of touch, as well as less pleasurable skin sensations, such as itch. The same optogenetics techniques that Dr. Lumpkin’s team applied to Merkel cells can now be applied to other skin cells to answer these questions.

“It’s an exciting time in our field because there are still big questions to answer, and the tools of modern neuroscience give us a way to tackle them,” she said.

Filed under sense of touch merkel cells neurons Piezo2 touch neuroscience science

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