Intracellular pH Determines How Cystic Fibrosis Protein Regulates Ion Transport

The protein cystic fibrosis transmembrane conductance regulator (CFTR) is responsible for maintaining the ion channels that move chloride ions and water into and out of cells, and mutations that prevent correct CFTR functioning can lead to the build up of the thick mucous that characterizes cystic fibrosis (CF).

Disease-causing mutations in the CFTR gene prevent the ion channel from functioning properly, leading to a blockage of the movement of salt and water into and out of cells. As a result of this blockage, cells that line the passageways of the lungs, pancreas, and other organs produce abnormally thick, sticky mucus. This mucus obstructs the airways and glands, causing the characteristic signs and symptoms of cystic fibrosis. In addition, while thin mucus can be removed by cilia, thick mucus cannot be removed by cilia, so it traps bacteria that give rise to chronic infections. Approximately 70,000 people worldwide have cystic fibrosis, the majority being children and young adults.

Investigators from the University of Bristol (United Kingdom) studied the effect of pH on CFTR, since changes in pH determine whether the ion channel is open or closed. The experiments were carried out using recombinant CFTR and excised membrane patches.

Results of the study were published in the December 18, 2009, issue of the Journal of Biological Chemistry. The authors reported that acidic pH increased the probability that wild-type CFTR would open the ion channel, whereas alkaline pH decreased this probability and inhibited flow of chloride ions through the channel. Acidic pH potentiated the MgATP (magnesium adenosine triphosphate) dependence of wild-type CFTR by increasing MgATP affinity and enhancing channel activity, whereas alkaline pH inhibited the MgATP dependence of wild-type CFTR by decreasing channel activity.

"The structure of CFTR resembles a turnstile - it has a pathway for chloride movement across the cell border and a gate that controls access to this pathway. Turning of the gate is powered by adenosine triphosphate, or ATP, an energy source for all cells,” explained senior author Dr. David Sheppard, professor of physiology and pharmacology at the University of Bristol. "This work demonstrates that intracellular pH regulates ATP docking with the gate and the speed at which the gate turns. The aim is to design and develop drug therapies that restore function to CFTR proteins disabled by CF mutations. By targeting the root cause of the disease, rather than the symptoms, new drug therapies for CF might stop disease progression and prevent the decline in health of individuals living with CF.”

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