Scientists
at the University of Washington in Seattle have determined the atomic
architecture of a sodium channel. The achievement opens new
possibilities for molecular medicine researchers around the world to
design better drugs for pain, epilepsy, and heart rhythm disturbances.
Sodium
channels are pores in the membranes of excitable cells—such as brain
nerve cells or beating heart cells—that emit electrical signals.
Sodium channels selectively open and close to allow the passage of
millions of tiny charged particles across the cell membrane. The gated
flow of sodium ions generates tiny amounts of electrical current.
Never
before have researchers been able to obtain a high-resolution crystal
structure showing all of the atoms of this complex protein molecule and
how they relate in three dimensions.
The
findings were reported in an advanced online edition of
Nature. The authors are Jian Payandeh, Todd Scheuer, Ning Zheng, and
William A. Catterall, all of the UW Department of Pharmacology. Zheng is
also a Howard Hughes Medical Institute investigator.
“Electrical
signals from voltage-gated sodium channels encode and process
information in the brain and nervous system, make heart muscle contract,
and control the release of insulin from the pancreas,” says Catterall,
UW chair and professor of pharmacology. “Sodium channels are important
molecules because they regulate a wide range of physiological
activities.”
Mutations
in voltage-gated sodium channels underlie inherited forms of epilepsy,
migraine headaches, heart rhythm disturbances, periodic paralysis, and
some pain syndromes. The symptoms of these disorders often stem from
faulty electrical signals between cells. In epilepsy, for example, an
electrical “storm” erupts in a network of cells in the brain. Some
nerve toxins, such as scorpion stings or hazardous algal blooms, disrupt
sodium channels. Many medications for pain, epilepsy and cardiac
arrhythmias—as well as for local and regional anesthesia—act on
sodium channels.
“When
you get a spinal block or your dentist gives you a numbing injection,
the local anesthetic drugs temporarily shut down sodium channels in the
area of the procedure and prevent your brain from receiving the bad news
from your nerves,” Catterall says.
Over more than three decades, Catterall’s lab and others at the UW have made many major discoveries about these tiny pores.
“But we had only a fuzzy, partial view of what the channels looked like,” he says. “Now we have a much more detailed picture.”
The
ability to visualize the atomic structural details of the sodium
channel was made possible by use of advanced methods of X-ray
crystallography and data analysis in the laboratory of Ning Zheng,
associate professor of pharmacology.
“A
major problem in studying sodium channels is that they want to be in a
cell membrane,” Catterall says. New biochemical techniques allowed the
research team to extract and purify bacterial sodium channels that they
had expressed in the cell membranes of insect cells, and keep them in a
stable, functional form for determination of their structure.
“Because
of the importance of the sodium channel, many labs have tried to work
on its atomic structure with no success,” Zheng says. “We succeeded
thanks to the collaborative approach we took and the right combination
of talent, expertise and resources.” Payandeh, the first author of the
paper, integrated expertise from both the Zheng and the Catterall
laboratories and his own past experience to tackle the challenge.
The structure emerged gradually over several months of laborious study.
“We
all thought ‘Eureka!’ but nobody said it,” Catterall says, recalling
when he and his colleagues realized what they had accomplished.
Examining
kinetic models of its intricate molecular structure will tell
scientists more about the biomechanics of a voltage-gated sodium
channel.
“We
hope to gain insight into why they selectively let in sodium ions and
nothing else,” the researchers say, “and how they respond to changes in
the cell membrane voltage, how they open and close, and how they
generate electrical signals.” The researchers have already spotted
intriguing molecular movement, such as rolling motions of some
functional parts of the sodium channel molecule and their connectors.
Knowing
how form affects function in sodium channels could lead to many new
ideas from scientists around the world on designing drugs to home in on
critical areas of the sodium channel molecule. The implications for drug
therapies are enormous.
For
example, the authors of the Nature paper unexpectedly discovered a
portal large enough for small pore-blocking drugs to enter the central
cavity of the sodium channel.
“There
is a lot of interest in drug design based on the structure of this
molecule and its binding sites,” Catterall says. “Scientists hope to
discover better drugs that exert their effects on specific targets
within the sodium channel. In particular, they want to find better pain
medications with fewer side effects and improved treatments for seizure
disorders and heart rhythm problems, such as those leading to sudden
cardiac death.”
In
1980 Catterall identified ion channel molecules for the first time by
locating the protein subunits of the sodium channel. Earlier, in the
1970s, his UW colleague Dr. Bertil Hille, professor of physiology and
biophysics, had analyzed the electrical signals produced by ion channels
and had proposed mechanistic models for their function. The new
structure reveals how the mechanistic models that Hille proposed work in
three dimensions.
After
more than 30 years of studying sodium ion channels, Catterall said the
ability to visualize the subject of his life-long research in incredibly
detailed 3D is “fantastic.”
