Opening or Closing These Cellular Portals Involves Much Smaller Movement Than Previously Thought
NEW YORK (August 31, 2005) — Tiny cellular doorways called ion channels are so small that scientists still have no way to directly view their activity. And yet dysfunctions in these microscopic portals help drive epilepsy, paralysis, cardiac arrhythmias, and other major disorders.
That's why a proper understanding of just how ion channels work to generate signaling between cells is crucial to understanding and treating disease.
Now, collaborative research by scientists at Weill Medical College of Cornell University in New York City and the University of California at Los Angeles may have greatly broadened that understanding. Their findings appear in the August 18 issue of Nature.
"We found that the molecular movement needed to 'open the gate' in potassium ion channels is much, much smaller than previously believed," said Dr. Benoit Roux, Professor of Physiology and Biophysics and Professor of Biochemistry at Weill Medical College of Cornell University.
Dr. Roux and UCLA researchers Dr. Baron Chanda and Dr. Francisco Bezanilla used a high-tech molecular fluorescence tracking system to confirm that just a tiny movement is needed for charged particles to open the potassium ion channel and then close it up again.
In fact, the Weill Cornell-UCLA paper is just one of three studies published in the August 18 issue of Nature supporting the "small movement" model, initially proposed by Dr. Bezanilla.
Every living cell contains microscopic ion channels — tiny portals that allow select molecules to pass through the cell's otherwise impermeable, protective outer membrane. Like toll booths on a busy highway, these channels open and close depending on specific signals. For neurons, especially, those signals are electrical in nature, with the passage of charged particles across the channel as the "key" that unlocks (or locks) the channel's gate.
However, there's always been one big problem in studying ion channel function: the structures are so incredibly small that no one has ever seen them in action.
"That means that we've had to devise theories, models, as to how they might work," Dr. Roux said.
One difficulty comes from the fact that the only quantity that's measurable via experiments is the amount of electrical work done by the channel gate as it opens. "Because this output mirrors that of simple electrical circuits, it was thought that the required 'gating charge' would traverse the entire membrane," Dr. Roux explained.
"Intuitively, this 'large-movement' model is the simplest picture that comes to mind, and it's a model that's been popular for decades," he said. "But our team at Weill Cornell developed a rigorous, 'small-movement' electrostatic theory for the gating charge years ago. It's gratifying to now apply this mathematical theory for the model deduced by the UCLA experiments."
Although the exact nature of this movement remains unclear, it's thought to involve the tilting of a corkscrew-shaped molecular structure called the "transmembrane helix," located inside a part of the ion channel called the "voltage sensor."
"Using small changes in voltage, you rotate the helix in a direction that's perpendicular to its axis to either open or close the gate," Dr. Roux explained. "It's what a friend of mine called the 'windshield wiper' model."
But just how big a tilt was needed? Dr. Roux's computational models suggested it might not be as broad a movement as once thought.
Focusing on a type of potassium channel called Shaker K+, Dr. Roux and the UCLA researchers used fluorescent molecular markers — the next best thing to a direct view of gating itself — to help them deduce the amount of movement involved.
"We found that you can have an effective 'gating' charge crossing the electrical potential without actually moving very much physically," Dr. Roux said. "It's possible that only a very small motion accounts for the gating change."
Large-motion theories have been in place for so long that "a lot of people are going to have a hard time accepting that," he said. However, two other studies published in the same issue of Nature also supported the small-movement view.
Why all this scientific fuss over a mechanism none of us may ever see?
"The function and dysfunction of these channels is so important to the life of the cell, and to the signalling between cells that governs both health and disease," Dr. Roux explained.
"Gating — the opening and closing of ion channels — is key to these processes. So, to understand why the gate is opening too easily, or with too much difficulty, you need to have a clear molecular picture of what's going on," he said. "Without actually seeing this activity directly, it's a leap of faith. But we just got a little bit surer."
The research was funded by fellowships and grants from the American Heart Association and the National Institutes of Health.
Co-researchers included Rikard Blunck, of UCLA, and Osei Kwame Asamoah, formerly of UCLA and now at the University of New Mexico Health Sciences Campus at Albuquerque.
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