July 01, 1999
Mathematics Reveals Inner Workings of Potassium Pipeline
Solving the three-dimensional structure of a potassium channel has allowed Roderick MacKinnon and colleagues to gain a better understanding of how the channel functions.
Many of the body's cells need a reliable flow of potassium to
perform their daily tasks. One key to potassium flow, now revealed to
researchers, appears to be the energetic effect of a pool of
approximately 50 water molecules and four protein spirals that sit in
the middle of a narrow channel embedded within cell membranes.
Roderick
MacKinnon, a Howard Hughes Medical Institute investigator at The
Rockefeller University, and chemist Benoit Roux at the University of
Montreal, arrived at this conclusion after calculating the electrical
forces operating at the center of the so-called potassium channel. This
mathematical analysis follows MacKinnon's team's determination of the
three-dimensional structure of a potassium channel last year. The
current work appears in the July 2, 1999, issue of the journal
Science.
The critical problem facing cells is that potassium — as well
as other small, charged entities known as ions — would rather be
surrounded by water than by the fatty substances that make up the cell
membrane. As MacKinnon explained, "these ions are equally stable in the
watery environments found inside or outside of the cell, but getting
from one side of the cell membrane to the other is like crossing a
large mountain.
"The result is that potassium does not cross the cell membrane
easily, no matter which direction it has to travel," he added.
Moving potassium through the cell membrane is critical to numerous
life-sustaining functions, including nerve signal generation,
heartbeat, and insulin release in response to changes in blood sugar.
For example, when a nerve signal travels the length of a neuron, large
amounts of potassium must be able to flow quickly from the inside to
the outside of a cell.
Last year, MacKinnon and his colleagues showed that the potassium
channel is essentially a pore-like structure containing four identical
proteins spanning the thickness of the cell membrane. Their studies
revealed that each of the four proteins folds together to form the pore
and that sections of each protein coil into spiral structures known as
a -helices.
One part of the channel, lying close to the outside of the cell
membrane, acts as a filter, allowing only potassium ions into the
channel. Four of the a -helices meet in the center of the pore and
point toward a cavity capable of holding a potassium ion and about 50
water molecules.
In their current study, MacKinnon and Roux's mathematical analysis
showed that the local electrical forces associated with the four
helices and the water molecules create an environment more like the
inside or outside of the cell than the typical center of a cell
membrane. This allows potassium to move quickly through the otherwise
unfavorable environment of the cell membrane.
"What this organization does is kind of level the energy mountain
separating the inside and outside of the cell. This is a very beautiful
design that nature has developed," said MacKinnon.
Though this research is "as basic as it gets," MacKinnon noted that
understanding the way the potassium channel functions may play an
important role in the development of drugs to deal with diseases
ranging from diabetes to heart problems. He said that improved
understanding of the channel's structure may allow researchers to
design medications that can restore the channel's proper functioning
should it go awry.
"If we can properly tune potassium channels, we could, for example,
develop new ways of affecting airway smooth muscle, which might have
implications for asthma," said MacKinnon.
Image: Chris Denney
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