Structural modeling of the voltage-sensing mechanism is important because it allows researchers to generate testable hypotheses and design new, highly specific drugs to treat a wide range of disorders, from chronic pain to epilepsy. The study is published in the Dec. 12 early edition of the Proceedings of the National Academy of Sciences.
Voltage-gated sodium channels are embedded in the plasma membranes of nerve and muscle cells. The channel consists of a large protein that allows sodium ions to pass when a change in voltage occurs across the cell membrane. While high-resolution structures of the voltage sensors that control ion-gate activation have been identified in an activated state, scientists need to know all of the conformational changes that occur throughout the cycle of activation and rest to develop better treatments for disease.
"Sodium channels transmit pain and are the sites of action of local anesthetics," said Vladimir Yarov-Yarovoy, an assistant professor of physiology and membrane biology at the UC Davis School of Medicine who developed the models in collaboration with researchers from the University of Washington in Seattle. "They are critical targets for new drug development for the treatment of chronic pain, epilepsy and other conditions caused by gain or loss-of-function mutations in voltage-gated sodium channels, which hyperexcite sensory neurons or attenuate action-potential firing causing pain or seizures."
Serious chronic pain affects at least 116 million Americans each year, and epilepsy affects nearly 3 million Americans and 50 million people worldwide. Yet, the treatment of chronic pain and epilepsy remains a major unmet medical need.
"Currently available drugs for these conditions have limited effectiveness and significant side effects," said Yarov-Yarovoy. "While the research community has focused on identifying selective inhibitors of sodium-channel subtypes in nerve, heart and muscle cells, no new therapies have advanced to clinical trials. The algorithm is an innovative approach that fosters the design of novel subtype-selective sodium channel blocking drugs that have high efficacy and minimal side effects to treat these disorders."
Yarov-Yarovy developed his high-resolution structural models using the Rosetta computational methods along with available X-ray crystallography and experimental data. The models sidestep a significant challenge to researchers -- the inability to obtain X-ray crystallography structures for the resting and intermediate states of the sodium channel because of their instability and the limitations of current X-ray crystallization techniques.
"To fully grasp the mechanism of voltage activation, we need to know more than one conformation of the voltage-sensing domain," said Benoít Roux, professor of biochemistry and molecular biophysics at the University of Chicago. "So far, X-ray crystallography has provided only the structure of the channel in the activated-state. The careful computational modeling developed by Yarov-Yarovoy is a powerful technique that is absolutely critical to advance our understanding of these systems."
The UC Davis School of Medicine is among the nation's leading medical schools, recognized for its research and primary-care programs. The school offers fully accredited master's degree programs in public health and in informatics, and its combined M.D.-Ph.D. program is training the next generation of physician-scientists to conduct high-impact research and translate discoveries into better clinical care. Along with being a recognized leader in medical research, the school is committed to serving underserved communities and advancing rural health. For more information, visit UC Davis School of Medicine at medschool.ucdavis.edu.
Carole Gan | EurekAlert!
Candidate Ebola vaccine still effective when highly diluted, macaque study finds
21.10.2019 | NIH/National Institute of Allergy and Infectious Diseases
Autism spectrum disorder risk linked to insufficient placental steroid
21.10.2019 | Children's National Hospital
After first reporting the existence of quantum knots, Aalto University & Amherst College researchers now report how the knots behave
A quantum gas can be tied into knots using magnetic fields. Our researchers were the first to produce these knots as part of a collaboration between Aalto...
Researchers have succeeded in creating an efficient quantum-mechanical light-matter interface using a microscopic cavity. Within this cavity, a single photon is emitted and absorbed up to 10 times by an artificial atom. This opens up new prospects for quantum technology, report physicists at the University of Basel and Ruhr-University Bochum in the journal Nature.
Quantum physics describes photons as light particles. Achieving an interaction between a single photon and a single atom is a huge challenge due to the tiny...
A very special kind of light is emitted by tungsten diselenide layers. The reason for this has been unclear. Now an explanation has been found at TU Wien (Vienna)
It is an exotic phenomenon that nobody was able to explain for years: when energy is supplied to a thin layer of the material tungsten diselenide, it begins to...
Researchers at Ludwig-Maximilians-Universitaet (LMU) in Munich have explored the initial consequences of the interaction of light with molecules on the surface of nanoscopic aerosols.
The nanocosmos is constantly in motion. All natural processes are ultimately determined by the interplay between radiation and matter. Light strikes particles...
Particles that are mere nanometers in size are at the forefront of scientific research today. They come in many different shapes: rods, spheres, cubes, vesicles, S-shaped worms and even donut-like rings. What makes them worthy of scientific study is that, being so tiny, they exhibit quantum mechanical properties not possible with larger objects.
Researchers at the Center for Nanoscale Materials (CNM), a U.S. Department of Energy (DOE) Office of Science User Facility located at DOE's Argonne National...
02.10.2019 | Event News
02.10.2019 | Event News
19.09.2019 | Event News
23.10.2019 | Materials Sciences
23.10.2019 | Physics and Astronomy
23.10.2019 | Medical Engineering