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But was it structural damage that made the mutant KCNJ5 channels leaky? Collaborating with Wenhui Wang at New York Medical College in Valhalla, Scholl answered the question experimentally. When she studied the mutant channels in cultured cell lines, she found that they allowed sodium ions to flow abnormally into the cells. The work was reported February 11, 2011, in Science.
Particularly notable to Lifton was how beautifully this story meshed with predictions made in the 1990s by fellow HHMI investigator Rod MacKinnon of Rockefeller University.
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Dedication Personified
Murim Choi spent his hours outside the lab learning computer programming.
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MacKinnon had shown that channel proteins allow only certain ions to pass through due to the configuration of protein building blocks that form a gate—a so-called “selectivity filter.” For that work, he was awarded the Nobel Prize in Chemistry in 2003.
“One mutation we found in KCNJ5 in tumors was in a residue that MacKinnon had defined as critical for potassium selectivity for similar channels,” says Lifton. MacKinnon’s work offers a satisfying architectural explanation for why sodium ions slip through the mutant channel, he adds.
The KCNJ5 story is the first report of an ion channel playing a role in the unbridled cell proliferation characteristic of tumors. Whether this knowledge will lead to less invasive treatment for adrenal tumors remains to be seen. In the meantime, Lifton envisions a simple blood test to detect KCNJ5 mutations to help diagnose this type of adrenal tumor.
Now, almost two decades after Lifton began his effort to discover the genetic basis of hypertension, his lab has identified 10 or so genes that when mutated increase blood pressure. All, including KCNJ5, control regulation of salt balance. He’s hoping these investigations will lead to better treatment strategies for the approximately 1 billion patients worldwide who have hypertension, a major risk factor for heart disease and stroke.
“To treat hypertensive disease, we often use three or more drugs per patient, and about two-thirds of those patients don’t improve under that kind of control,” says Lifton. “We must figure out a better way to treat these patients.”
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