To print: Select File and then Print from your browser's menu --------------------------------------------------------------------------------------- Title: Researchers Advance Understanding of the Ion Channel Involved in Cystic Fibrosis URL: http://www.pslgroup.com/dg/394A6.htm Doctor's Guide September 17, 1997
IOWA CITY, IA. -- September 17, 1997 -- Researchers at Howard Hughes Medical Institute are challenging a commonly held theory about how cystic fibrosis with research which may lead to new treatments for the most common hereditary disease in the United States. Cystic fibrosis is caused by the malfunction of an ion channel critical for maintaining the secretions of salt and water that protect the lungs. 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 the Sept. 18 issue of 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 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 the R domain simply blocked the channel pore like a cork, thus inhibiting the flow of chloride. This model states 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 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 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 said. "So it is not simply an on-off switch." Welsh and Winter believe 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 motor. "This finding has increased our understanding of how the CFTR chloride channel works," Welsh said. "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." --------------------------------------------------------------------------------------------- Copyright © 1999 P\S\L Consulting Group Inc. All rights reserved. Republication or redistribution of P\S\L content is expressly prohibited without the prior written consent of P\S\L. 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