The most sensitive of these cells “react to mechanical changes on their surface in the order of magnitude of a few millionths of a millimeter,” said Dr. Poole. “For a pain-sensitive cell to respond – it functions like a mechanoreceptive cell – a considerably stronger stimulus is needed,” the biologist said, explaining the latest experiments of the MDC researchers. These findings could be important to develop new therapies for people with neuropathic pain, for example, for shingles. For these patients, the slightest touch is painful.
In their previous work the Berlin researchers showed that the mechanoreceptive cells are crucial for the sensation of touch – but only in the context of their surroundings, the so-called matrix and its constituent molecules. Pressure or movement of the skin acts on both the matrix and the embedded nerve endings simultaneously.
To unlock the secrets of the sense of touch, the scientists created an artificial system that mimics real-world conditions. It looks like a tiny nail cushion just a few thousandths of a millimeter in size. This system allows very fine and defined mechanical stimuli to be exerted on mechanosensitive cells – via their connection with the matrix. Simultaneously with matrix movement the researchers can directly measure the electrical response of the cell.
Dr. Poole and the research team were amazed to find that if one single nail within the special nail cushion is displaced by just a ten millionth of a millimeter, mechanosensitive cells react and transduce the stimulus, in the intact organism to the brain.
Apparently, mammals have groups of touch sensors with different levels of sensitivity. Pain-sensitive cells from the skin of the mouse, however, must be mechanically stimulated 1000 times stronger before they are activated. “That makes sense,” said study leader Professor Lewin, “otherwise we would often feel pain unnecessarily.”
In a second step, the MDC researchers wanted to know what molecules mediate the significantly different sensitivity of touch and pain sensory cells. The result: a protein named Stoml3 substantially controls the variation in the sensitivity to mechanical stimuli. “When the gene for Stoml3 is inactivated,” Dr. Poole said, “the differences in mechanosensitivity sensitivity almost completely disappear.” According to the findings of the MDC researchers, Stoml3 modulates the activity and sensitivity of two so-called ion channels in the membranes of many different cell types. These ion channels are called Piezo1 and Piezo2. “Our findings strongly indicate that Piezo2 is involved in touch perception and transduces the appropriate signals, under powerful regulatory control by Stoml3,” Professor Lewin added.
Understanding how Stoml3 works exactly could open up new ways to combat neuropathic pain. The researchers are seeking to block the hypersensitive touch sensors in the skin of patients. According to Lewin, Stoml3 provides a very good target for this. A potentially interesting aspect of this study: An anesthetic injection, e.g. by the dentist, numbs all feeling in the tissue. By contrast, this new form of therapy would only inhibit the conversion of mechanical stimuli into electrical signals. “Otherwise you could continue to feel everything,” said Lewin, “heat, cold, and so on.”
*Tuning Piezo ion channels to detect molecular-scale movements relevant for fine touch
Kate Poole1,*, Regina Herget1, Liudmila Lapatsina1, Ha-Duong Ngo2 and Gary R. Lewin1,*
Affiliations:1 Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Straße 10, D-13092 Berlin, Germany.
2Microsensor & Actuator Technology, Technische Universität Berlin, D-13355 Berlin, Germany.
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
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