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
Enduring cold temperatures alters fat cell epigenetics
19.04.2018 | University of Tokyo
Full of hot air and proud of it
18.04.2018 | University of Pittsburgh
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
In an article that appears in the journal “Review of Modern Physics”, researchers at the Laboratory for Attosecond Physics (LAP) assess the current state of the field of ultrafast physics and consider its implications for future technologies.
Physicists can now control light in both time and space with hitherto unimagined precision. This is particularly true for the ability to generate ultrashort...
The Atlantic overturning – one of Earth’s most important heat transport systems, pumping warm water northwards and cold water southwards – is weaker today than any time before in more than 1000 years. Sea surface temperature data analysis provides new evidence that this major ocean circulation has slowed down by roughly 15 percent since the middle of the 20th century, according to a study published in the highly renowned journal Nature by an international team of scientists. Human-made climate change is a prime suspect for these worrying observations.
“We detected a specific pattern of ocean cooling south of Greenland and unusual warming off the US coast – which is highly characteristic for a slowdown of the...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
19.04.2018 | Power and Electrical Engineering
19.04.2018 | Life Sciences
18.04.2018 | Materials Sciences