Key step in bicarbonate secretion might lead to novel cystic fibrosis treatments

By Aline McKenzie

Researchers at UT Southwestern have uncovered the underlying mechanism in the body that coordinates the secretion of bicarbonate — also known as baking soda — from the pancreas and other organs, a process that is essential for dissolving digestive enzymes and mucus proteins and for neutralizing stomach acids.

The research, in The Journal of Clinical Investigation, has potential applications for developing new therapies for cystic fibrosis (CF), a life-threatening genetic disease in which patients suffer from thick mucus and other secretions that clog their lungs, pancreas and intestines.

The research team of Dr. Shmuel Muallem (left) and Dr. Dongki Yang studied a protein called IRBIT, the master controller of bicarbonate secretion.

In 2001, Dr. Shmuel Muallem, professor of physiology, and his colleagues discovered that dysfunctional bicarbonate secretion from cells lining the pancreas and lungs plays a key role in CF. The pancreas, lungs and intestine normally secrete fluids that contain a high concentration of bicarbonate, which makes the fluids alkaline. Without bicarbonate, however, these fluids become acidic and cannot dissolve digestive enzymes and mucus, which is what happens in CF patients.

“Cystic fibrosis patients are deficient in this process, which is vital in so many body secretory systems,” said Dr. Muallem.

Implications for patients

Patients with CF usually require frequent hospitalizations and treatments, and while their life expectancy has increased dramatically over the years, few with the disease live beyond their 20s or 30s.

In the current study, Dr. Muallem’s group found that a protein called IRBIT is the master controller of bicarbonate secretion. It controls the activity of another protein, called CFTR, which normally helps move bicarbonate and other molecules through tissues. Dr. Muallem’s team previously has shown that mutations in CFTR are responsible for malfunctions in bicarbonate transport.

IRBIT already was known to activate another molecule involved in bicarbonate secretion called pNBC1.

When the researchers blocked the action of IRBIT in cultured mouse pancreatic ducts, they found that this prevented bicarbonate and fluid from being secreted into the ducts.

“Without IRBIT, neither of these proteins were activated, so no bicarbonate or fluid made it into the ducts,” said Dr. Muallem, senior author of the study. “One of the most serious problems in cystic fibrosis is the lack of bicarbonate that is essential for dissolving large proteins like digestive enzymes and mucins, found in mucus, and for neutralizing stomach acids.”

The researchers found that different portions of IRBIT normally attach to the CFTR and pNBC1 molecules, suggesting that treatments focusing on these differing regions in IRBIT may be useful in reducing the severity of cystic fibrosis, said Dr. Muallem.

Other researchers

Other UT Southwestern researchers involved in the study were Dr. Dongki Yang, postdoctoral researcher in physiology; Dr. Nikolay Shcheynikov, assistant instructor of physiology; Dr. Weizong Zeng, assistant professor of physiology; and Ehud Ohana, research associate in physiology. Researchers from Seoul National University College of Medicine in South Korea, the RIKEN Brain Science Institute in Japan and the Japan Science and Technology Agency also participated.

The study was funded by the Cystic Fibrosis Foundation and the National Institutes of Health.

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Dr. Muallem holds the Ruth S. Harrell Professorship in Medical Research.