Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Atomic structure discovered for a sodium channel that generates electrical signals in living cells

14.07.2011
The achievement opens new possibilities for designing drugs for pain, epilepsy and heart rhythm disturbances

Scientists at the University of Washington (UW) in Seattle have determined the atomic architecture of a sodium channel. The achievement opens new possibilities for molecular medicine researchers around the world in designing better drugs for pain, epilepsy, and heart rhythm disturbances.

Sodium channels are pores in the membranes of excitable cells – such as brain nerve cells or beating heart cells – that emit electrical signals. Sodium channels selectively open and close to allow the passage of millions of tiny charged particles across the cell membrane. The gated flow of sodium ions generates tiny amounts of electrical current.

Never before have researchers been able to obtain a high-resolution crystal structure showing all of the atoms of this complex protein molecule and how they relate in three-dimensions.

The findings were reported in the July 10 advanced online edition of Nature. The authors are Jian Payandeh, Todd Scheuer, Ning Zheng, and William A. Catterall, all of the UW Department of Pharmacology. Zheng is also a Howard Hughes Medical Institute investigator.

"Electrical signals from voltage-gated sodium channels encode and process information in the brain and nervous system, make heart muscle contract, and control the release of insulin from the pancreas," said Catterall, UW chair and professor of pharmacology. "Sodium channels are important molecules because they regulate a wide range of physiological activities."

Mutations in voltage-gated sodium channels underlie inherited forms of epilepsy, migraine headaches, heart rhythm disturbances, periodic paralysis, and some pain syndromes.

The symptoms of these disorders often stem from faulty electrical signals between cells. In epilepsy, for example, an electrical "storm" erupts in a network of cells in the brain. Some nerve toxins, such as scorpion stings or hazardous algal blooms, disrupt sodium channels.

Many medications for pain, epilepsy and cardiac arrhythmias –as well as for local and regional anesthesia -- act on sodium channels.

"When you get a spinal block or your dentist gives you a numbing injection, the local anesthetic drugs temporarily shut down sodium channels in the area of the procedure and prevent your brain from receiving the bad news from your nerves," Catterall said.

Over more than three decades, Catterall's lab and others at the UW have made many major discoveries about these tiny pores.

"But we had only a fuzzy, partial view of what the channels looked like," he said. "Now we have a much more detailed picture."

The ability to visualize the atomic structural details of the sodium channel was made possible by use of advanced methods of X-ray crystallography and data analysis in the laboratory of Ning Zheng, associate professor of pharmacology.

"A major problem in studying sodium channels is that they want to be in a cell membrane," Catterall said. New biochemical techniques allowed the research team to extract and purify bacterial sodium channels that they had expressed in the cell membranes of insect cells, and keep them in a stable, functional form for determination of their structure.

"Because of the importance of knowing the atomic structure of sodium channels, many labs have tried to work on it with no success," Zheng said. "We succeeded thanks to the collaborative approach we took and the right combination of talent, expertise, and resources." Payandeh, the first author of the paper, integrated expertise from both the Zheng and Catterall labs and his own past experience to tackle the challenge.

The structure emerged gradually over several months of laborious study.

"We all thought 'Eureka!' but nobody said it," Catterall said, recalling when he and his colleagues realized what they had accomplished.

Examining kinetic models of its intricate molecular structure will tell scientists more about the biomechanics of a voltage-gated sodium channel.

"We hope to gain insight into why they selectively let in sodium ions and nothing else," the researchers said, "and how they respond to changes in the cell membrane voltage, how they open and close, and how they generate electrical signals." The researchers have already spotted intriguing molecular movement, such as rolling motions of some functional parts of the sodium channel molecule and their connectors.

Knowing how form affects function in sodium channels could lead to many new ideas from scientists around the world on designing drugs to home in on critical areas of the sodium channel molecule. The implications for drug therapies are enormous.

For example, the authors of the Nature paper unexpectedly discovered a portal large enough for small pore-blocking drugs to enter the central cavity of the sodium channel.

"There is a lot of interest in drug design based on the structure of this molecule and its binding sites," Catterall said. "Scientists hope to discover better drugs that exert their effects on specific targets within the sodium channel. In particular, they want to find better pain medications with fewer side effects and improved treatments for seizure disorders and heart rhythm problems, such as those leading to sudden cardiac death."

In 1980 Catterall identified ion channel molecules for the first time by locating the protein subunits of the sodium channel. Earlier, in the 1970s, his UW colleague Dr. Bertil Hille, professor of physiology and biophysics, had analyzed the electrical signals produced by ion channels and had proposed mechanistic models for their function.

The new structure reveals how the mechanistic models that Hille proposed work in three dimensions.

After more than 30 years of studying sodium ion channels, Catterall said the ability to visualize the subject of his life-long research in incredibly detailed 3-D is "fantastic."

The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. Payandeh received support from a Canadian Institutes of Health Research fellowship.

The authors declared no competing financial interests.

Leila Gray | EurekAlert!
Further information:
http://www.washington.edu

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>