Dr. Jeffrey Balser (left) discusses research results with post-doctorate fellow Prakash Viswanathan. (photo by Dana Johnson)
Table salt found to block crucial potassium channels
Vanderbilt University Medical Center investigators have discovered a new molecular cause for sensitivity to low potassium.
One of the key electrolytes floating around in the bloodstream, potassium can be a killer. Not enough of it, or too much of it, provokes dangerous arrhythmias.
Writing in the May issue of Nature Neuroscience, the investigators report that sodium blocks a crucial potassium channel called HERG, an effect that is especially powerful when there is little or no potassium around.
"It was a surprise that the sodium — the table salt — in our bloodstream really wants to block the HERG channel completely. That's unprecedented for a potassium channel," said Dr. Jeffrey R. Balser, James Taloe Gwathmey Clinician-Scientist, associate professor of Anesthesiology and Pharmacology and associate dean for Physician-Scientist Development.
HERG channels, donut-like pores that let potassium cross the cell membrane, are especially important in the electrically excitable cells of the heart and brain. And when they don't work correctly, individuals are at risk for a life-threatening cardiac arrhythmia known as Torsades de pointes, and may also be at risk for seizures.
Genetic mutations that produce a faulty HERG channel are associated with a disorder called "long QT syndrome" that predisposes patients to the potentially fatal Torsades de pointes. Drugs that block the HERG channel have the same effect.
"The number of drugs that block HERG and can cause Torsades de pointes is very large," Balser said. "The FDA is now insisting that almost all new drugs that are marketed be tested for their HERG-blocking potential. So the whole issue surrounding HERG and its regulation is becoming a major issue in biomedical science and pharmacology."
Balser's interest in the HERG channel was sparked by the channel's strange behavior. Others had shown that raising the potassium concentration outside a cell dramatically increases the electrical current (potassium moving) through the HERG channel.
"But, we would expect that if we raise potassium outside the cell, the driving force for potassium to go through the HERG channel would go down, and therefore the current should get smaller," Balser said.
"Instead, the current gets huge. That was puzzling–how can raising external potassium make currents bigger when they should get smaller?"
Sleepless nights as a medical resident also made Balser well aware of the importance of serum potassium levels.
"Every house officer gets a lot of calls for potassium," he said. "Patients in the intensive care unit, who are on a lot of drugs that can block HERG, are at exceptional risk for arrhythmias. Keeping potassium levels up is a major part of the care of critically ill patients.
"So as a physician-scientist, I found HERG particularly appealing. It was clearly clinically relevant and was also a puzzle from a biophysical standpoint."
Balser and his colleagues found that raising potassium outside the cell only increases the HERG current when sodium is also present.
They concluded that the potassium outside the cell is actually regulating sodium blockade of the HERG channel in order to fine-tune HERG current, and therefore cellular excitability.
"Right now, if you didn't have any potassium in your bloodstream to get in sodium's way, all of your HERG channels would be completely blocked by sodium, and you would be in serious trouble," he said.
Of course, most healthy individuals are not at risk for having low levels of potassium. But individuals who are taking diuretics — high blood pressure or heart failure patients — are continuously losing potassium.
If given a drug that blocks HERG, these patients may be at exceptional risk for arrhythmias.
"The current work helps us understand why people are so sensitive to potassium and helps us look for ways, other than raising potassium, to overcome that sensitivity — ways to stop the table salt from attacking our HERG channels," Balser said.
Alternatives to raising potassium are important because the electrolyte has a very narrow therapeutic range. High potassium concentrations also provoke arrhythmias.
Balser's group will seek alternatives by examining how sodium blocks the HERG channel.
"If we understand how sodium blocks current through the HERG channel, we may be able to develop safer drugs that increase HERG currents and protect people at risk for seizures and arrhythmias," he said.
Balser's colleagues in the departments of Anesthesiology and Pharmacology are Hirotaka Numaguchi, Ph.D., J.P. Johnson Jr., Ph.D., and Christina I. Petersen, Ph.D. The work was supported by the National Institutes of Health and the American Heart Association.