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Inside out. The old model (top) put the voltage sensitive paddles inside the pore of the channel. New research shows they're on the outside.

Molecular Toggle Switch

As you scan this article, nerve cells in your eyes are furiously sending signals to your brain. Like all neurons, these cells rely on proteins that control the flow of ions into and out of the cell. New work unveils one such ion channel's structure, which is striking in its simplicity yet completely unexpected.

To send an electrical impulse down the length of a nerve fiber, neurons depend on ion channels embedded in their membranes that open and close in response to changes in the voltage difference between the inside and outside of the cell. Although scientists have studied the functions of these channels for decades, their three-dimensional structure has proved difficult to pin down. To visualize a protein's structure, biologists analyze the x-ray diffraction pattern of the purified, crystallized protein. However, extracting a protein from inside the cell membrane requires treatment with detergent, which then coats the protein and makes crystallization difficult. Another problem is the flexibility of these proteins, which prevent the formation of a rigid crystal.

To circumvent this problem, biophysicists Youxing Jiang and Roderick MacKinnon at Rockefeller University in New York City and their colleagues anchored the floppy arms of the protein with antibodies, allowing them to crystallize it and look at its structure. They discovered that the four paddle-shaped regions of the protein that sense voltage changes stick out into the cell membrane, rather than being tucked into the core of the channel, as originally suspected.

The researchers tested how these paddles react to changes in voltage by attaching a small molecule to different parts of the paddle, then situating the modified channel in a flattened-out membrane. By tracking the position of the attached molecule as they changed the voltage across the membrane, the researchers put together a picture of how the ion gating mechanism works. When the inside of the cell becomes positively charged, the positively charged edge of each paddle drifts from the cell-facing side of the membrane to the outward-facing side. Like a lever, it pulls the central pore of the channel open as it swings from one side to the other, allowing potassium ions to stream out of the cell, the team reports in two papers in the 1 May issue of Nature. The researchers expect that the channel, obtained from the archaebacterium Aeropyrum pernix, operates the same way as voltage-gated channels in mammals.

"This is an amazing body of work," says physiologist Fred Sigworth of Yale University. He says that the voltage-sensor paddle model seems "simple and obvious" in hindsight, but adds that the problem of how the positively charged paddles position themselves within the oily interior of the cell membrane, rather than seeking out a watery environment, as their chemistry would dictate, remains to be explained.

Related sites
Roderick MacKinnon's Web site
Fred Sigworth's Web site
MacKinnon's prior work describing the structure of a potassium channel (ScienceNOW, 6 April 1998)