A new study conducted by researchers at the University of Arizona College of Medicine-Phoenix and University of California Davis Health found a new target for developing a drug to treat atrial fibrillation (AFib or AF), an irregular heart rhythm. The most common type. ,

The American Heart Association estimates that more than 12 million people will have AFib by 2030, and current treatment approaches are inadequate, researchers say.

Proteins involved in the physiological processes of the heart have been the target of AFib research for some time. Until recently, most research suggested that treating AFib through inhibition of specific small-conductance calcium-activated potassium channels or SK channels could reduce or worsen arrhythmias under various circumstances.

“Our study used pioneering experimental and computational approaches to understand how the human SK2 channel is dynamically co-regulated,” said Nipawan Chiamwimonwat, MD, chair of the Department of Basic Medical Sciences at the U of A College of Medicine-Phoenix. How can it be done? The study is particularly timely considering that inhibitors of SK channels are currently in clinical trials to treat AFib, making further insight into their regulatory mechanisms paramount.

For the study, researchers examined the role of the lipid, phosphatidylinositol 4,5-bisphosphate, or PIP2, in regulating the SK2 channel. PIP2 is an integral part of the cell membranes of all plants and animals and acts as a messenger for various signaling pathways in the body.

Ryan Woltz, PhD, computational biologist and co-first author of the paper and an assistant research professor at the College of Medicine-Phoenix, said, “Because PIP2 plays such an important role in many ion channels, cardiac ion channels function through PIP2. Regulating κ presents a new mechanism for lipid regulation of cardiac excitation and function.

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

“Since PIP2 is known to be dysregulated in heart failure, our study provides important translational insight into potential mechanisms,” said Yang Zheng, PhD, postdoctoral research fellow at the College of Medicine-Phoenix and co-first author. cardiac arrhythmias In heart failure.

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

“Structural insights from our study will be useful in designing new inhibitors of SK2 channels to treat cardiac arrhythmias,” said Vladimir Yarov-Yarovoy, PhD, professor at UC Davis Health.

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

“I am thrilled to participate in this collaborative multi-university and multi-disciplinary research study and look forward to continued collaboration,” Vorobyov said. We are currently working on applying a similar pioneering experimental/computational approach to the modulation of SK channels by drugs. Molecules that can enhance or inhibit the function of these ion channels may be used as potential treatment options for AFib and other heart diseases.

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