Potential therapeutic target for cardiac arrhythmias found in SK2 channels

A new study led by researchers at the University of Arizona College of Medicine in Phoenix and University of California Davis Health has identified a new target for developing a treatment to treat atrial fibrillation, the type the most common abnormal heart rhythm.

Atrial fibrillation, commonly called AFib or AF, causes approximately 1 in 7 strokes, according to the U.S. Centers for Disease Control and Prevention, and is associated with a significant increase in risk of morbidity and mortality. According to the American Heart Association, more than 12 million people are expected to have atrial fibrillation by 2030, and current treatment paradigms remain inadequate, researchers say.

Proteins involved in physiological processes in the heart have been a target of AFib research for some time. Until recently, most research suggested that treating atrial fibrillation through inhibition of specific low-conductance calcium-activated potassium channels, or SK channels, could reduce or worsen arrhythmias in different conditions.

“Our study used pioneering experimental and computational approaches to decipher how the human SK2 channel may be dynamically co-regulated. The study is particularly timely considering that SK channel inhibitors are currently being used. “are in clinical trials to treat atrial fibrillation, making deeper insight into their regulatory mechanisms paramount,” said Nipavan Chiamvimonvat, MD, chair of the Department of Basic Medical Sciences at University of Phoenix Medicine.

The article titled “Atomistic mechanisms of regulation of the small conductance Ca2+-activated K+ channel (SK2) by PIP2” was published in the journal Proceedings of the National Academy of Sciences.

The research team examined the role of a lipid, phosphatidylinositol 4,5-bisphosphate, or PIP2, in regulating the SK2 channel. PIP2 is an integral part of all plant and animal cell membranes and acts as a messenger for various signaling pathways in the body.

“Since PIP2 plays an essential role in multiple ion channels, regulation of cardiac ion channels via PIP2 presents a novel mechanism for lipid regulation of cardiac excitability and function,” said computational biologist Ryan Woltz, Ph.D. ., co-first author of the article. author and assistant research professor at the College of Medicine – Phoenix.

Currently, SK channels are the only known potassium channels that are upregulated in heart failure, and their regulation plays a critical role in cardiac excitability and how cardiac rhythm disturbances develop.

“Since PIP2 is known to be dysregulated in heart failure, our study provides critical translational insights into the possible mechanisms of cardiac arrhythmias in heart failure,” said co-first author Yang Zheng, Ph.D., postdoctoral researcher at the College of Medicine – Phénix.

Using comparative modeling, the research team generated models of human SK2 channels in closed, intermediate, and open states. They then used molecular dynamics simulations to explore the molecular mechanisms of SK2 channel modulation by PIP2.

“The structural information from our study will be useful for designing new SK2 channel inhibitors to treat cardiac arrhythmias,” said Vladimir Yarov-Yarovoy, Ph.D., professor at UC Davis Health.

Co-senior author Igor Vorobyov, Ph.D., associate professor at UC Davis Health, said the team is already using similar computational approaches to study other SK channel subtypes.

“I am excited to participate in this multi-university, multi-disciplinary collaborative research study and look forward to continued collaboration,” Vorobyov said. “We are currently working on the application of a similar pioneering experimental/computational approach to the modulation of SK channels by drug molecules, which can enhance or inhibit the function of these ion channels and can be used as prospective treatment options for the atrial fibrillation and other cardiovascular diseases.”