Whether stubbing a toe or stroking a cat, the sensation of touch starts out as a mechanical force that is then transformed into an electrical signal conveying pain or other sensations. Tiny channels in neurons act as translators by helping to formulate that signal to the brain. However, scientists know little about the fine details of how these channels work.
New work at Rockefeller University has revealed that one such channel in humans responds to mechanical force using a never-before-seen mechanism. Researchers led by Roderick MacKinnon, John D. Rockefeller Jr. Professor and head of the Laboratory of Molecular Neurobiology and Biophysics examined the TRAAK channel, which is involved in painful touch sensation, at the molecular and atomic levels, finding that it works by reducing the flow of potassium ions that create an electrical signal. The researchers’ findings were released yesterday (December 3) in Nature.
Molecular roadblock: The TRAAK channel (purple and orange) dampens sensations by letting potassium ions escape from a neuron. Researchers found the channel uses a never-before-seen system for blocking that flow of ions when it closes: A lipid (yellow) from the neuron membrane (gray) protrudes into the channel.
”It is fascinating to wonder how living cells evolved molecules capable of turning small mechanical forces, such as those associated with touch, into electrical signals in the nervous system. That question served as the impetus for this work,” MacKinnon says.
The channels that act as gates in the membranes that envelop neurons, including TRAAK, allow electrically charged atoms, called ions, to move in or out. It’s this movement that is the basis for an electrical signal that carries information.
TRAAK channels are one of 78 types of channels in the human body that transport potassium ions; there are other devoted to other ion types. By allowing potassium to trickle out of the neuron, TRAAK normally quiets the neurons, balancing out other channels, which would otherwise create a strong electrical signal for pain.
“TRAAK acts kind of like the brakes on a painful touch sensation, while other channels act as the gas. If you take away the brakes, innocuous touch becomes painful,” says first author Stephen Brohawn, a postdoc in the lab.
Prior work in the lab has shown TRAAK responds to membrane tension – that is stretching caused by a physical force. However, it wasn’t clear how this force caused the channel to open. In fact, scientists had previously only explained the workings of two mechanical-force sensing channels, both of which are found in bacteria.
After purifying the protein that makes up TRAAK, the team crystallized it and determined its structure using X-ray diffraction analysis. Based on the pattern produced by X-rays bounced off the crystallized protein, scientists can infer the structure of the molecule. But because it is difficult to get high-quality crystals from TRAAK, the researchers used antibodies that targeted it to create a sort of scaffold to help guide the formation of crystals.
In the structural images revealed by this work, the researchers found a unique system is responsible for holding off the flow of ions. TRAAK’s central cavity, through which the ions must pass, is flanked by two spiral-shaped chains called helices. When both of these chains are kinked upward, the channel is open so potassium can leave the cell. But when one of these two chains relaxes downward, it uncovers a sort of side door into the center of the neuron membrane.
Neuron membranes, like all cell membranes, consist of two layers of molecules called lipids that have heads facing outward and greasy chains extending inward. When TRAAK’s side door is open, one of those greasy chains, called an acyl chain, pokes into TRAAK’s central cavity, blocking it so no potassium can pass. No known channel uses a mechanism like this.
“This is the first time anyone has seen, at a molecular level, how mechanical force can open a channel in animals, including humans,” Brohawn says. “When the membrane stretches, TRAAK widens, sort of like a dot on a balloon that expands as it is inflated. That wider conformation pulls the helices upward, preventing an acyl chain from blocking the channel, and so leaving it open for potassium ions.”
“The direct involvement of lipid molecules in the gating mechanism begins to explain another well-known property of TRAAK channels – that their gating is sensitive to general anesthetics and other molecules known to enter the lipid membrane where they insert themselves between its acyl chains. By doing so, it appears these anesthetics can shut down pain sensations by locking TRAAK in an open position,” MacKinnon says.
Zach Veilleux | newswise
Transport of molecular motors into cilia
28.03.2017 | Aarhus University
Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
28.03.2017 | Life Sciences
28.03.2017 | Information Technology
28.03.2017 | Physics and Astronomy