CONTACT: L. E. OHMAN
283 Medical Laboratories
Iowa City IA 52242
(319) 335-6660; fax (319) 335-8034
Release: Embargoed until 2 p.m. EST 9/17/97
UI researchers advance understanding of ion channel in cystic fibrosis
IOWA CITY, Iowa -- Cystic fibrosis, the most common hereditary disease
in the United States, is caused by the malfunction of an ion channel that
is critical for maintaining the secretions of salt and water that protect
Work by Dr. Michael Welsh, Howard Hughes Medical Institute Investigator
and UI professor in the department of internal medicine, and Dr. Michael
Winter, working in Welsh's laboratory, suggests a novel way in which this
ion channel may function, thus challenging a commonly held "corked/uncorked"
theory. Their finding, published in Thursday's issue of the journal Nature
paves the way for a more refined research effort to find a cure or improve
treatment for cystic fibrosis.
The cystic fibrosis transmembrane conductance regulator (CFTR) protein
makes a chloride channel. Chloride passes through this channel while sodium
moves through a parallel channel. This simultaneous movement of ions keeps
the lungs healthy by controlling the salt (sodium chloride) concentration
in the lung fluid.
The gene that makes the CFTR protein is mutated in people who have cystic
fibrosis. The mutation results in a chloride channel that does not open
to allow chloride flow. Consequently, the concentration of salt is abnormal.
This interferes with the normal lung defense mechanisms that kill bacteria
and keep the lungs sterile.
Scientists know that the part of the CFTR protein called a regulatory,
or R domain, is involved in the opening and closing of the channel. Before
the Welsh and Winter experiment, it was thought that the R domain simply
blocked the channel pore like a cork, thus inhibiting the flow of chloride.
This model states that the channel is "uncorked" when a phosphate
molecule attaches to the R domain in a process called phosphorylation.
When Welsh and Winter tested this "cork" model, they discovered
that the mechanism controlling chloride flow through the channel is more
complex than originally thought.
To examine the role of the R domain in the opening and closing of the
chloride channel, they removed it from the CFTR protein in the laboratory
using genetic engineering. They then did a three-part study looking at
chloride flow when 1) no R domain was present , 2) a non-phosphorylated
R domain was added back and 3) after a phosphorylated R domain was
added back. Each experiment produced unexpected results.
First, the "cork" model predicts that with no R domain, the
channel would act like it was open most of the time. However, in experiment
one, the channel did not open as much as would be expected if the plug
had been removed from the pore.
When the researchers added back a non-phosphorylated R domain
in experiment two, they predicted that the channel would be blocked--but
again were surprised. The non-phosphorylated R domain did not act as a
cork to plug the channel.
Finally, the most interesting results came when Welsh and Winter added
back phosphorylated R domain to the chloride channels. Rather than
having no effect on ion flow as predicted by the "cork" model,
the phosphorylated R domain actually increased channel opening.
"Our results show that the R domain does not function solely as
an inhibitor that keeps the channel closed," Welsh says, "so
it is not simply an on-off switch."
Welsh and Winter believe that rather than directly controlling chloride
flow through the channel by acting like a cork, the R domain acts as an
enabler for a compound called ATP. Binding of this compound to the CFTR
protein is responsible for opening the channel, and phosphorylation of
the R domain makes it easier for ATP to bind. When the R domain is not
phosphorylated, less ATP binds to it, and the channel closes.
In the model proposed by Welsh and Winter, the part of the channel that
binds ATP can be compared to a motor that opens the channel. The phosphorylated
R domain allows the motor to run faster and cause the channel to open more.
It may be that the R domain increases delivery of the fuel, ATP, to the
"This finding has increased our understanding of how the CFTR chloride
channel works," Welsh says. "The more we understand about how
things work normally and why they don't work in people who have cystic
fibrosis, the closer we are to developing new treatments."
Note to editors: Dr. Welsh is currently out of town, but can be reached
by calling his secretary Theresa at (319) 335-7619.