The rapid-fire opening and closing of potassium channels, necessary for triggering neuronal signals and heartbeats, has been a topic of abiding interest. How, scientists wondered, could these channels fire potassium ions across the cell membrane with such startling efficiency?

Long thought to fly though the potassium channel in single file, potassium ions have been supposed to travel in chain, abiding ion-to-ion contact, or interspersed with water molecules, spurning ion-to-ion contact. At least since 2003, the latter mechanism has been favored. At that time, American biochemist Roderick MacKinnon, M.D., was awarded a Nobel Prize for his work elucidating the potassium channel’s structural details. Dr. MacKinnon suggested, and subsequent work supported, the idea that ion-to-ion contact was unlikely due to high electrostatic repulsion.

Now, however, results have has emerged that challenge this view. According to researchers at the University of Dundee, the Max Planck Institute for Biophysical Chemistry, the University of Göttingen, and the University of Oxford, water is not co-transported though the channels with ions and is not needed to separate the potassium ions. Instead, the researchers found that pairs of potassium ions are stably formed and then pass through the channel, with electrostatic repulsion driving the efficiency of the process.

These results appeared October 17 in the journal Science, in an article entitled, “Ion permeation in K+ channels occurs by direct Coulomb knock-on.”

“By analyzing more than 1,300 permeation events from molecular dynamics simulations at physiological voltages, we observed instead that permeation occurs via ion-ion contacts between neighboring K+ ions,” wrote the authors. “Coulomb repulsion between adjacent ions is found to be the key to high-efficiency K+ conduction. Crystallographic data are consistent with directly neighboring K+ ions in the selectivity filter, and our model offers an intuitive explanation for the high throughput rates of K+ channels.”

In Science, a perspective article (“Potassium ions line up”) by Gerhard Hummer, Ph.D., notes that the new findings harken back to a classic 1955 study by Hodgkin and Keynes, who proposed a “knock-on” mechanism—a single file of closely packed potassium ions shuttling though the channel, a “hard” approach not softened by intervening water. This model, however, appeared to conflict with experimental results that include electrophysiological data.

According to a press release issued by the University of Dundee, the new results manage to get around these problems because they went beyond previous work, which was limited to looking at static or closed-state crystal structures: “Advances in computing have allowed researchers to now look at the channels ‘in action,’ which have provided much more detail and revealed the workings of the channels.”

“Our findings explain how potassium flux is able to happen at the maximum physically attainable speed, which is vital for the fast response of neurons,” said Ulrich Zachariae, Ph.D., Reader in Computational Biophysics and Drug Discovery at the University of Dundee.

“This is a paradigm shift in the field. It changes our understanding of how these hugely important channels work. These channels are tremendously important as they are active in all cells so it is vital that we understand how they work.”

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