|
"The effects of many toxins and therapeutic drugs,
as well as some diseases, can be wholly explained by changes in ion
channel function," says Story Landis, Ph.D., director of the National
Institute of Neurological Disorders and Stroke (NINDS), part of the
NIH. "We also know that ion channels are at least a contributing
player in epilepsy, chronic pain, Parkinson's disease and other
disorders. As we learn more about how channels work, we're able to
pursue more approaches to treatment."
Ion channels are proteins
that control the flow of electrically charged salt particles (ions)
across the nerve cell membrane. It's the opening and closing of these
channels that enables nerve cells to fire off bursts of electrical
activity. A built-in voltmeter, called a voltage sensor, pops the
channel open when the nerve cell is ready to fire. The papers in
Nature hone in on a part of the voltage sensor called the paddle,
named for its shape.
In the first study, a team led by NINDS senior
investigator Kenton Swartz, Ph.D., shows that the paddle works as a
modular unit. Using recombinant DNA technology, they swapped the
paddle from an ion channel found in an ancient, volcano-dwelling
bacterium to a channel found in rat brain. As long as the paddle was
intact, the hybrid channel still worked. This portability could one
day be exploited to test potential drugs. For example, researchers who
want to target a paddle from a poorly characterized ion channel could
stick it into a well-studied channel where the effects of drugs are
easier to measure.
Other results in the paper suggest that the paddle
itself will be a useful target for new therapeutic drugs. Dr. Swartz's
group found that the paddle is the docking site for certain toxins in
tarantula venom, which are known to interfere with ion channel opening.
There are hints that scorpions, sea anemones and cone snails make
similar toxins, Dr. Swartz said. If nature has found ways to
manipulate ion channel function, medicinal chemists might be able to
do the same, he said.
In the second study, supported by the National
Institute of General Medical Sciences (NIGMS), researchers took
advantage of the paddle's unique transplantability to create a hybrid
ion channel ideal for structural studies. Led by Roderick MacKinnon,
M.D. � a Nobel Laureate, an investigator of the Howard Hughes Medical
Institute and a biophysicist at Rockefeller University in New York �
the team produced data that explain how the voltage sensor is
positioned within the membrane and how it triggers channel opening.
"The determination of the three-dimensional
structures of ion channels has yielded a framework to understand their
fascinating functional properties," says NIGMS director Jeremy M.
Berg, Ph.D. "These new results show how clever experimental designs
can focus on key questions and steer the direction of additional
studies." |
