If you put a sponge in water it swells, and the same is true of cells. But take on too much water and a cell will burst. Fortunately, nature has devised a mechanism to help cells deal with the challenges of a variable environment.

“If you eat a bag of salty potato chips or drink a jug of water, the cells lining your stomach will be under pressure to shrink or expand,” said Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics and professor of internal medicine (nephrology). “Cells need to rapidly change their ionic composition to compensate and avoid blowing up like balloons or shrinking like raisins, and they do this by almost instantly changing their chloride levels.”

Lifton and his coworkers reported in the journal Cell in August that they had determined how cells control their chloride concentration in response to such changes in their surroundings. The team’s findings explain a fundamental process of cell volume regulation and have implications for such diseases as sickle cell anemia and nervous system disorders.

The researchers knew that when cells sense a dip in salt concentrations outside their membranes, they activate a protein embedded in the cell membrane that pumps out chloride and potassium ions. Water follows the salt, and that fluid loss stops the cells from swelling. A modification of that protein acts as an on/off switch, first author and Associate Research Scientist Jesse Rinehart, Ph.D., found. Adding two phosphate groups to the protein turns it off while their absence turns on the ion transporter. The same transport protein is present in most cells; Rinehart found it even in neurons, in which the concentration of chloride regulates the neurons’ response to neurotransmitters rather than to cell size.

What turns the switch? Rinehart and colleagues identified an enzyme, the WNK1 kinase, which is responsible for adding the critical phosphate groups. Interestingly, the Lifton lab had previously found WNK kinases to be master regulators of electrolyte flux in the kidney, where changes in the kinases’ activity level can lead to high blood pressure.

Understanding how the switch works may suggest new treatments for sickle cell anemia, according to coauthor Patrick G. Gallagher, M.D., professor of pediatrics (neonatology). Transporter activity is known to be hyperactive in red blood cells from people with sickle cell disease. That increased activity causes dehydration of the red blood cells, which increases the chances that the sickle hemoglobin molecules will clump and the cells will break up. Dehydrated sickle cells are also more likely to stick to blood vessel walls and block blood flow. “Now that we know how the transporter works, we can find the regulators that control it. The transporter and its regulators are fertile ground for identifying potential drug targets to treat sickle cell disease,” said Gallagher.

According to Lifton, the discovery was possible because Yale is home to a large proteomics center, one of 10 funded in 2002 by the National Heart, Lung, and Blood Institute. Working at the center, Rinehart was able to apply the latest proteomics techniques to analyze the transporter. “We wouldn’t have been able to get into this line of work without the center,” Lifton says. “It was a big help to us.”