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Research project yields better understanding of the defective protein that causes cystic fibrosis

protein back to its correct location, on the cell border, and second, when CFTR is defective, restoring function to it.

"CFTR itself is a small passageway with a gate, called an ion channel, found on the surface of cells lining ducts and tubes, where it acts as a pathway for the movement of chloride ions, one component of salt, and regulates the transport of bicarbonate, one part of soda," Chen explained.

By adjusting the transport of these molecules, he said, CFTR regulates the acid-base balance, or pH, of cells; and precise control of intracellular pH is vital for the function of all cells.

"In the case of cells lining ducts and tubes, intracellular pH regulates salt transport, protects the body against foreign invaders -- such as bacteria -- and controls cell survival," Chen said.

While scientists have had evidence that CFTR regulates pH in cells, it had been unknown how it detected changes in pH and knew when to adjust its activity. So, Chen set out to test his idea that CFTR activity is directly regulated by intracellular pH itself.

He successfully demonstrated that acid pH potently stimulates chloride transport by CFTR, whereas alkali pH inhibits it. To learn how pH regulates chloride transport via CFTR, Chen studied the function of the individual building blocks from which CFTR is assembled.

"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 David Sheppard, who oversaw Chen's work as a doctoral student in the department of physiology and pharmacology at the University of Bristol. "Jeng-Haur's work demonstrates that intracellular pH regulates ATP docking with the gate and the speed at which the gate turns."

Thus, intracellular pH determines the power level at the gate, which, in t

Contact: Angela Hopp
American Society for Biochemistry and Molecular Biology

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