A new study by researchers at the University of Arizona College of Medicine — Phoenix and the University of California Davis Health has identified a new target for developing a therapy to treat atrial fibrillation (AFib), the most common type of abnormal heart rhythm. AFib causes about 1 in 7 strokes, leading to a significant increase in the risk of morbidity and mortality. It is estimated that more than 12 million people will have AFib by 2030, and current treatment options are considered inadequate. The study focused on the role of small-conductance calcium-activated potassium channels, known as SK channels, in the development of AFib and explored how these channels can be regulated.
Proteins involved in the physiological processes of the heart have been a key area of research for AFib, with prior studies suggesting that inhibiting SK channels could have varying effects on arrhythmias. The researchers used experimental and computational approaches to understand how the human SK2 channel can be co-regulated dynamically. They specifically examined the role of a lipid called phosphatidylinositol 4,5-bisphosphate (PIP2) in regulating the SK2 channel, which plays a crucial role in modulating cardiac excitability and function. By studying the molecular mechanisms of SK2 channel modulation by PIP2, the team aimed to provide insights into developing novel therapies for cardiac arrhythmias.
Currently, SK channels are the only known potassium channels that are upregulated in heart failure, suggesting their regulation is critical in cardiac excitability and rhythm disturbances. The dysregulation of PIP2 in heart failure further underscores the importance of understanding how lipid regulation impacts cardiac arrhythmias. Through comparative modeling and molecular dynamics simulations, the researchers generated human SK2 channel models in different states and explored the structural insights that could be used to design new inhibitors of SK2 channels for treating cardiac arrhythmias.
The study published in the journal Proceedings of the National Academy of Sciences shed light on the critical role of PIP2 in the regulation of the SK2 channel and how dysregulation of this lipid may contribute to cardiac arrhythmias. The team is now working on using similar computational approaches to study other subtypes of SK channels, with the goal of developing prospective treatment options for AFib and other cardiovascular diseases. By understanding how lipid regulation affects cardiac ion channels, the researchers hope to pave the way for novel therapies that can effectively target and treat atrial fibrillation.
The study’s findings provide new insights into the molecular mechanisms underlying the regulation of SK2 channels and highlight the potential of developing novel therapies for treating atrial fibrillation. By deciphering how PIP2 modulates the SK2 channel, the researchers have identified a promising target for developing drugs that can effectively regulate cardiac excitability and function. Through collaborative efforts and innovative experimental approaches, the team aims to advance the field of cardiovascular research and develop new treatment options for patients with AFib and other related conditions.