Study Will Boost Therapeutic Options for Patients with Cardiac Arrhythmias

H. Peter Larsson, Ph. D., associate professor of physiology and biophysics, led a study published in the April issue of Nature Communications that brings researchers one step closer to understanding the mechanism behind cardiac arrhythmias caused by mutations in the IKs channel, a physiologically important potassium channel critical in controlling the heart’s electrical activity.

“Understanding IKs channel functioning will lead to better treatments of life-threatening cardiac arrhythmias,” said Larsson, who is senior author.

For the study, “KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps,” Larsson and Rene Barro-Soria, Ph.D., postdoctoral scholar and first author, used independent methods to investigate the pore-forming subunits KCNQ1 and KCNE1 that comprise the IKs channel and how KCNE1 affects the activation kinetics of these channels.

Responsible for the slowly activating potassium current that contributes to the repolarization of the cardiac action potential, loss-of-function mutations in KCNQ1 or KCNE1 have been linked to Long QT syndrome, a heart disorder that can lead to ventricular arrhythmias, ventricular fibrillation and sudden cardiac death.

Using two independent methods – voltage clamp fluorometry and cysteine accessibility – the investigators found that KCNE1 separates the voltage sensor movement of KCNQ1 into two components.

“Our results show that KCNE1 separates the voltage sensor (S4) movement of the KCNQ1 channel into two components – a rapid S4 movement that occurs at negative voltages well before channel opening and a slow S4 movement that occurs at positive voltages and parallels channel opening,” Larsson explained.

Many models have been proposed to explain how KCNE1 interacts with KCNQ1 to alter the channel properties, which Larsson says is currently a matter of intense debate.

Is the activation of KCNQ1/KCNE1 channels slow because KCNE1 slows the movement of the voltage sensors, because KCNE1 slows the opening of the gate, or a combination of both?

Larsson and his team, unlike those before them, have devised a model that can successfully and repeatedly reproduce the same results – a promising advancement in understanding the complex channels.

“Our goal is to understand the mechanism behind cardiac arrhythmias caused by mutations in IKs channels, which will lay the groundwork for developing future therapeutic agents to treat these arrhythmias,” Larsson said.

The research was funded by the National Institutes of Health (R01–HL095920 and R01-GM109762), a James & Esther King Biomedical Research grant to Larsson, and an American Heart Association postdoctoral fellowship grant (13POST17000057) to Barro-Soria.

Co-authors of the study include Santiago Rebolledo, Ph.D., former postdoctoral associate; Sara I. Liin, Ph.D., postdoctoral fellow; Marta E. Perez, M.S., research associate; and Kevin J. Sampson, Ph.D., and Robert S. Kass, Ph.D., from Columbia University Medical Center.

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