Researchers have discovered a lipid that plays a key role in controlling heart ion channels, shedding light on potential mechanisms behind cardiac arrhythmias in heart failure and opening avenues for future therapeutic advancements.
A groundbreaking study conducted by researchers at the University of Arizona College of Medicine – Phoenix and the University of California Davis Health has highlighted a new target for potential therapies aimed at treating atrial fibrillation, the most prevalent type of irregular heartbeat.
Atrial fibrillation, often referred to as AFib, is responsible for approximately 1 in 7 strokes, as reported by the U.S. Centers for Disease Control and Prevention. It is linked to a considerably higher risk of serious health complications and death. The American Heart Association predicts that over 12 million individuals will be affected by AFib by the year 2030, but existing treatment approaches remain insufficient, according to researchers.
For some time, research has focused on proteins that play a role in the heart’s physiological functions concerning AFib. Until recently, studies indicated that targeting specific small-conductance calcium-activated potassium channels, or SK channels, to treat AFib might either alleviate or exacerbate arrhythmias, depending on the circumstances.
“Our research employed innovative experimental and computational methods to unravel how the human SK2 channel can be dynamically regulated. This study is particularly relevant as SK channel inhibitors are currently undergoing clinical trials for AFib treatment, making further understanding of their regulatory mechanisms essential,” commented Nipavan Chiamvimonvat, MD, chair of the Department of Basic Medical Sciences at the U of A College of Medicine – Phoenix.
The research paper, titled “Atomistic Mechanisms of the Regulation of Small Conductance Ca2+-Activated K+ Channel (SK2) by PIP2,” has been published in the journal Proceedings of the National Academy of Sciences.
The team investigated the role of a lipid known as phosphatidylinositol 4,5-bisphosphate, or PIP2, in regulating the SK2 channel. PIP2 is a crucial component found in all plant and animal cell membranes and acts as a signaling messenger for various pathways within the body.
“As PIP2 is essential in regulating multiple ion channels, its influence on cardiac ion channels presents a new avenue for understanding how lipids regulate heart excitability and function,” stated Ryan Woltz, PhD, a computational biologist and co-first author of the study, who is also an assistant research professor at the College of Medicine – Phoenix.
Currently, SK channels are the only potassium channels known to be upregulated in heart failure, and their regulation is critical in maintaining cardiac excitability and in the development of rhythm disturbances in the heart.
“The dysregulation of PIP2 in heart failure highlights the importance of our findings, offering valuable insights into potential mechanisms behind cardiac arrhythmias in such conditions,” noted co-first author Yang Zheng, PhD, a postdoctoral research fellow at the College of Medicine – Phoenix.
Utilizing comparative modeling, the research team created models of the human SK2 channel in its closed, intermediate, and open configurations. They then applied molecular dynamics simulations to investigate how PIP2 modulates the SK2 channel at a molecular level.
“The structural insights gained from our study could facilitate the development of new SK2 channel inhibitors that may be effective in treating cardiac arrhythmias,” explained Vladimir Yarov-Yarovoy, PhD, a professor at UC Davis Health.
Co-senior author Igor Vorobyov, PhD, an associate professor at UC Davis Health, mentioned that the team is already employing similar computational strategies to examine other types of SK channels.
“I am excited to be part of this collaborative multi-university and multidisciplinary research initiative, and I look forward to extending our collaboration,” Vorobyov said. “We are currently investigating how drug molecules can modulate SK channels, potentially enhancing or inhibiting their function, which could lead to new treatment options for AFib and other cardiovascular illnesses.”
According to computational biologist Ryan Woltz, PhD, who is an assistant research professor at the College of Medicine — Phoenix and co-first author of the study, the discovery of how cardiac ion channels are regulated by PIP2 reveals a new aspect of lipid influence on heart activity and function.
At present, SK channels are the only potassium channels known to be increased in heart failure, and their regulation is essential for maintaining heart excitability and managing rhythm disturbances.
Co-first author Yang Zheng, PhD, a postdoctoral research fellow at the College of Medicine — Phoenix, noted that as PIP2 regulation is disrupted in heart failure, this research offers important insights into potential mechanisms behind cardiac arrhythmias associated with heart failure.
The research team created human SK2 channel models in various states—closed, intermediate, and open—using comparative modeling. They employed molecular dynamics simulations to investigate how PIP2 modulates the SK2 channel.
Vladimir Yarov-Yarovoy, PhD, a professor at UC Davis Health, explained that the structural insights gained from this study could aid in developing new SK2 channel inhibitors aimed at treating cardiac arrhythmias.
Igor Vorobyov, PhD, an associate professor at UC Davis Health and co-senior author, mentioned that the team is also applying similar computational techniques to examine other SK channel subtypes.
“I am excited to be a part of this collaborative research involving multiple universities and disciplines, and I look forward to continuing our partnerships,” Vorobyov stated. “We are currently investigating the modulation of SK channels through drug molecules using an innovative experimental and computational approach, which could potentially enhance or inhibit these ion channels, offering new treatment avenues for AFib and other heart conditions.”
Researchers from the University of Arizona College of Medicine — Phoenix and the University of California Davis Health have pinpointed a new target for developing therapies for atrial fibrillation (AFib), which is the most prevalent form of irregular heart rhythm.
AFib is linked to approximately 1 in 7 strokes, as reported by the U.S. Centers for Disease Control and Prevention, and poses a significant risk for increased morbidity and mortality. By 2030, it’s estimated that over 12 million people will suffer from AFib, according to the American Heart Association, highlighting the inadequacy of current treatment strategies.
For some time, proteins that contribute to the heart’s physiological processes have been a focal point in AFib research. Recent studies have indicated that inhibiting specific small-conductance calcium-activated potassium channels (SK channels) may have varying effects on arrhythmias based on conditions.
Dr. Nipavan Chiamvimonvat, chair of the Department of Basic Medical Sciences at the U of A College of Medicine — Phoenix, remarked, “Our research utilized groundbreaking experimental and computational methods to unravel the dynamic co-regulation of the human SK2 channel. This investigation is particularly relevant as inhibitors of SK channels are currently being tested in clinical trials for AFib, making insights into their regulatory mechanisms crucial.”
The article titled “Atomistic Mechanisms of the Regulation of Small Conductance Ca2+-Activated K+ channel (SK2) by PIP2” was published in the Proceedings of the National Academy of Sciences.
The research team analyzed the influence of phosphatidylinositol 4,5-bisphosphate, or PIP2, a lipid that regulates the SK2 channel. PIP2, a vital component of all plant and animal cell membranes, serves as a signaling messenger in various pathways within the body.
Ryan Woltz, PhD, emphasized that the modulation of cardiac ion channels through PIP2 introduces a new understanding of lipid regulation concerning heart excitability and function.
Currently, upregulation of SK channels is unique to heart failure, and their regulation significantly affects heart excitability and the emergence of rhythm disturbances.
Yang Zheng, PhD, reiterated that because PIP2 is disrupted in heart failure, this research provides essential insights into the potential mechanisms of cardiac arrhythmias in affected patients.
The team modeled the SK2 channel in various states and used molecular dynamics simulations to probe how PIP2 affects these channels.
Vladimir Yarov-Yarovoy, PhD, noted that findings from this research could be instrumental in creating new SK2 inhibitors for treating cardiac arrhythmias.
Igor Vorobyov, PhD, confirmed that similar computational strategies are being employed for analyzing other SK channel types.
“I’m eager to continue this collaborative effort across universities and disciplines,” Vorobyov concluded. “Our ongoing research aims to study the modulation of SK channels by drug molecules, which may improve or inhibit the functions of these ion channels, presenting promising treatment options for AFib and various cardiovascular diseases.”
