We can distinguish between the roughness of sandpaper and the much finer texture of a silk cloth through vibrations detected by our fingers as they move across a surface. This sense is incredibly acute: our fingers can detect structures that are too small to be seen with the naked eye, or even the most powerful light microscopes. A recent study by Gary Lewin’s group, published in the journal Nature Communications, sheds light on some of the molecular and cellular mechanisms that permit us to perceive vibrations on an extremely fine scale.
“Ultimately these sensations are due to changes detected by specific nerve cells,” Gary says. “As you run your fingers across a textured surface, pressure pushes and stretches cells, then relaxes again. Nerves translate these changes into electrochemical signals that are ultimately passed along to the brain and interpreted as vibrations. Our work aimed to pin down the molecular mechanisms by which cells perceive such extremely tiny changes in pressure.”
Generating such signals requires that the cell change its own electrical properties; it does so by taking up and releasing charged particles called ions. Channels in the cell membrane briefly open to permit ions to pass through. So ultimately the fluttering sensation of vibrations is the result of a very rapid opening and closing of membrane channels. They act like switches to turn the nerve into a transmitter, switch it off again, and repeat the process very rapidly.
The current study was headed by Kate Poole, a postdoc from Gary’s lab. Kate’s position and her work are tangible outcomes of her receipt of the first Cécile Vogt fellowship. This program was developed by the MDC to help talented women scientists establish their independence.
“Understanding how neurons sense vibrations required answering several different questions,” Kate says. “First we had to identify the membrane channel that was being used – cells have over 300 types of ion channels, made of different proteins. Many of these channels were known, but they aren’t sensitive enough to respond on their own to very tiny changes in pressure on the cell membrane.”
Earlier work by Gary’s lab had grown neurons in cell cultures and shown that they respond to pressure exerted on either the soma – the main cell body – or brushy, branch-like dendrites that they extend into the skin. But instruments scientists had been using to press on the cells and measure their responses weren’t small enough or sensitive enough to observe the very fine changes that underlie our perception of vibrations.
Kate and other members of the group solved this technical problem by growing nerves on a surface made of an elastomeric silicon material. Its surface was molded into arrays of tiny “pillars” that can be moved a millionth of a millimeter to nudge a cell’s soma or a specific dendrite. After deflecting a pillar, the scientists used a method called patch-clamp to measure very local changes in a cell’s electrical charge. Such measurements are so precise that they reflect differences caused by the opening and closing of a single membrane channel.
The new technique permitted extremely fine, precise disturbances of the cell surface. “Imagine pushing on a surface with something blunt, like the eraser on a pencil,” Kate said. “Now we were pushing with ‘needles’ whose movements were so small they couldn’t be seen under the microscope. Even these tiny applications of pressure provoked strong, fast currents.” Such currents switched on and off very quickly, which you would expect – running your fingers over a bumpy surface will probably press and release the same nerves many times.
What type of ion channel was responsible for switching the nerves from a quiet state to an active one, in response to pressure? Membrane channels can be built from multiple copies of a single protein, or various molecules woven together to form a pore-like structure that can open and close. These proteins ultimately determine what type of stimulation the channel responds to and how it behaves.
Previous work by Gary’s lab and others had shown that mice lacking a protein called STOML3 lost the behavior normally associated with touch. Using the “pillar assay” method developed by Kate, the scientists showed that cells needed STOML3 to detect very fine structures. But it wasn’t directly part of the channel; instead, it was controlling whether the pore opened or closed.
Other groups had discovered that a protein called Piezo, found in these neurons, might build channels sensitive to changes in pressure. These channels had responded to the rather blunt pressure of previous methods, but acting alone, they couldn’t detect the much finer structures we feel as vibrations. The scientists removed Piezo proteins from neurons and discovered that they became almost completely insensitive to fine vibrations. Cells that had Piezo but no STOML3 were also desensitized. This meant that STOML3 was acting as a sort of “fine tuner” that made the Piezo channels about 10 times more sensitive.
Further experiments showed that STOML3 has a direct contact with Piezo proteins in these nerve cells. “This gives us a new model of the way we sense vibrations, particularly very fast ones caused by the tiniest surface structures our fingers can detect,” Gary says. “These sensations cause subtle changes of pressure on the cell membrane which are sensed by STOML3. This protein opens ion channels made of Piezo proteins and causes the nerve to transmit an electrochemical signal to the brain. The whole system resets itself very quickly to send another signal.”
Developing this scheme, he says, wouldn’t have been possible without the new method invented by Kate and the team. It adds an important new tool to their arsenal of techniques – one which will be useful in many projects to come.
- Russ Hodge
Poole K, Herget R, Lapatsina L, Ngo HD, Lewin GR. Tuning Piezo ion channels to detect molecular-scale movements relevant for fine touch. Nat Commun. 2014 Mar 24;5:3520. doi: 10.1038/ncomms4520.