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

Proteins involved in physiological processes of the heart have been a target of research for AFib 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 either reduce or worsen arrhythmias under different conditions.

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

The paper, “Atomistic Mechanisms of the Regulation of 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 component of all plant and animal cell membranes and acts as a messenger for a variety of signaling pathways in the body.

“Because PIP2 plays such an essential role in multiple ion channels, regulating cardiac ion channels through PIP2 presents a new mechanism for the lipid regulation of cardiac excitability and function,” said computational biologist Ryan Woltz, PhD, the paper’s co-first author and an 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 disturbances in the heart’s rhythm develop.

“Since PIP2 is known to be dysregulated in heart failure, our study provides critical translational insights into possible mechanisms of cardiac arrhythmias in heart failure,” said co-first author Yang Zheng, PhD, a postdoctoral research fellow at the College of Medicine — Phoenix.

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

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

Co-senior author Igor Vorobyov, PhD, an 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 multidisciplinary research study and looking forward to a continued collaboration,” Vorobyov said. “We are currently working on applying a similar pioneering experimental/computational approach to modulation of SK channels by drug molecules, which may enhance or inhibit function of these ion channels and can be used as prospective treatment options for AFib and other cardiovascular diseases.”

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

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

Proteins involved in physiological processes of the heart have been a target of research for AFib 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 either reduce or worsen arrhythmias under different conditions.

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

The paper, “Atomistic Mechanisms of the Regulation of Small Conductance Ca2+-Activated K+ channel (SK2) by PIP2,” was published in the journal Proceedings of the National Academy of Science.

The research team examined the role of a lipid — phosphatidylinositol 4,5-bisphosphate, or PIP2 — in regulating the SK2 channel. PIP2 is an integral component of all plant and animal cell membranes and act

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

Proteins involved in physiological processes of the heart have been a target of research for AFib 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 either reduce or worsen arrhythmias under different conditions.

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

The paper, “Atomistic Mechanisms of the Regulation of 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 component of all plant and animal cell membranes and acts as a messenger for a variety of signaling pathways in the body.

“Because PIP2 plays such an essential role in multiple ion channels, regulating cardiac ion channels through PIP2 presents a new mechanism for the lipid regulation of cardiac excitability and function,” said computational biologist Ryan Woltz, PhD, the paper’s co-first author and an 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 disturbances in the heart’s rhythm develop.

“Since PIP2 is known to be dysregulated in heart failure, our study provides critical translational insights into possible mechanisms of cardiac arrhythmias in heart failure,” said co-first author Yang Zheng, PhD, a postdoctoral research fellow at the College of Medicine — Phoenix.

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

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

Co-senior author Igor Vorobyov, PhD, an 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 multidisciplinary research study and looking forward to a continued collaboration,” Vorobyov said. “We are currently working on applying a similar pioneering experimental/computational approach to modulation of SK channels by drug molecules, which may enhance or inhibit function of these ion channels and can be used as prospective treatment options for AFib and other cardiovascular diseases.”

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

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

Proteins involved in physiological processes of the heart have been a target of research for AFib 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 either reduce or worsen arrhythmias under different conditions.

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

The paper, “Atomistic Mechanisms of the Regulation of Small Conductance Ca2+-Activated K+ channel (SK2) by PIP2,” was published in the journal Proceedings of the National Academy of Science.

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

“Because PIP2 plays such an essential role in multiple ion channels, regulating cardiac ion channels through PIP2 presents a new mechanism for the lipid regulation of cardiac excitability and function,” said computational biologist Ryan Woltz, PhD, the paper’s co-first author and an 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 disturbances in the heart’s rhythm develop.

“Since PIP2 is known to be dysregulated in heart failure, our study provides critical translational insights into possible mechanisms of cardiac arrhythmias in heart failure,” said co-first author Yang Zheng, PhD, a postdoctoral research fellow at the College of Medicine — Phoenix.

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

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

Co-senior author Igor Vorobyov, PhD, an 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 multidisciplinary research study and looking forward to a continued collaboration,” Vorobyov said. “We are currently working on applying a similar pioneering experimental/computational approach to modulation of SK channels by drug molecules, which may enhance or inhibit function of these ion channels and can be used as prospective treatment options for AFib and other cardiovascular diseases.”

“In the past, researchers would ask participants to recall what they were doing when they lost their balance, but memory can be unreliable,” said Madigan. “With this new method, participants record their experiences immediately after an incident, providing much more accurate and detailed information.”

The findings were recently published in the Journal of American Geriatrics Society and highlight how voice-recorders captured the moment when participants, who averaged around 72 years of age, lost their balance. The study concludes that among older adults, voice recorders are effective at capturing the circumstances and context in which they lost their balance and potentially fell, without relying on recall later.

Partners:

• Michael Madigan, professor with the Grado Department of Industrial and Systems Engineering at Virginia Tech
• Neil Alexander, director, VA Ann Arbor Health Care System GRECC; University of Michigan: Ivan Duff Collegiate Professor of Geriatric and Palliative Medicine, Department of Internal Medicine; Research Professor, Institute of Gerontology

Real-world insight

In this study, 30 participants wore voice recorders on their wrists over the course of three weeks, and in the event of balance loss, turned them on to record answers to these key questions:

• When and where did the balance loss occur?
• What were they doing at the time?
• How did they attempt to regain their balance — did they grab a railing, take steps, or sit down?
• Why do they think they lost their balance?
• Did they fall?

This immediate, self-reported data was analyzed by Madigan and his team. Instead of waiting to meet with researchers after losing their balance, participants could reflect on what happened in the moment.

“We’re trying to better understand the circumstances in which people lose their balance,” Madigan said. “This process doesn’t require people to think back weeks or months to an incident, especially when memory can be unreliable.”

Participant experience

Maria Moll, a retired epidemiologist and study participant, found the research particularly meaningful, especially as someone in her 70s who remains physically active. After a friend experienced a fall, Moll became more interested in contributing to balance-loss prevention research.

“I’ve always been interested in physical fitness and balance, especially as I age,” said Moll. “This study made me more mindful of my movements, particularly during more challenging activities like hiking.”

The future of real-world data collection

Looking ahead, the team plans to expand the study to larger groups and combine the data with other lab-based measurements. By doing so, they hope to identify individuals who are most at risk of balance loss and develop strategies to proactively address those risks.

“We want to give clinicians the tools to intervene before a fall occurs,” said Madigan. “This method can provide more reliable, detailed information that helps us understand not just how people lose their balance, but why.”

In the study, published in the October issue of the journal Brain, researchers observed that ophthalmic acid binds to and activates calcium-sensing receptors in the brain, reversing the movement impairments of Parkinson’s mouse models for more than 20 hours.

The disabling neurogenerative disease affects millions of people worldwide over the age of 50. Symptoms, which include tremors, shaking and lack of movement, are caused by decreasing levels of dopamine in the brain as those neurons die. L-dopa, the front-line drug for treatment, acts by replacing the lost dopamine and has a duration of two to three hours. While initially successful, the effect of L-dopa fades over time, and its long-term use leads to dyskinesia — involuntary, erratic muscle movements in the patient’s face, arms, legs and torso.

“Our findings present a groundbreaking discovery that possibly opens a new door in neuroscience by challenging the more-than-60-year-old view that dopamine is the exclusive neurotransmitter in motor function control,” said co-corresponding author Amal Alachkar, School of Pharmacy & Pharmaceutical Sciences professor. “Remarkably, ophthalmic acid not only enabled movement, but also far surpassed L-dopa in sustaining positive effects. The identification of the ophthalmic acid-calcium-sensing receptor pathway, a previously unrecognized system, opens up promising new avenues for movement disorder research and therapeutic interventions, especially for Parkinson’s disease patients.”

Alachkar began her investigation into the complexities of motor function beyond the confines of dopamine more than two decades ago, when she observed robust motor activity in Parkinson’s mouse models without dopamine. In this study, the team conducted comprehensive metabolic examinations of hundreds of brain molecules to identify which are associated with motor activity in the absence of dopamine. After thorough behavioral, biochemical and pharmacological analyses, ophthalmic acid was confirmed as an alternative neurotransmitter.

“One of the critical hurdles in Parkinson’s treatment is the inability of neurotransmitters to cross the blood-brain barrier, which is why L-DOPA is administered to patients to be converted to dopamine in the brain,” Alachkar said. “We are now developing products that either release ophthalmic acid in the brain or enhance the brain’s ability to synthesize it as we continue to explore the full neurological function of this molecule.”

Team members also included doctoral student and lab assistant Sammy Alhassen, who is now a postdoctoral scholar at UCLA; lab specialist Derk Hogenkamp; project scientist Hung Anh Nguyen; doctoral student Saeed Al Masri; and co-corresponding author Olivier Civelli, the Eric L. and Lila D. Nelson Chair in Neuropharmacology — all from the School of Pharmacy & Pharmaceutical Sciences — as well as Geoffrey Abbott, professor of physiology & biophysics and vice dean of basic science research in the School of Medicine.

The study was supported by a grant from the National Institute of Neurological Disorders and Stroke under award number NS107671 and the Eric L. and Lila D. Nelson Chair in Neuropharmacology.

Alachkar and Civelli are inventors on a provisional patent that covers products related to ophthalmate and calcium-sensing receptors in motor function.

The study, led by first author Debanjan Bhattacharya, PhD, was recently published in the journal Cancers.

Research background

According to the American Cancer Society, lung cancer is the leading cause of cancer death in the United States, accounting for about one in five cancer deaths. Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, making up approximately 80% to 85% of all lung cancer cases.

Up to 40% of lung cancer patients develop brain metastases during the course of the disease, and these patients on average survive between eight and 10 months following diagnosis.

Current standard of care treatments for lung cancer that spreads to the brain include surgical resection and stereotactic brain radiosurgery, and whole brain irradiation is standard in patients with more than 10 metastatic brain lesions.

“Lung cancer brain metastasis is usually incurable, and whole brain radiation treatment is palliative, as radiation limits therapy due to toxicity,” said Bhattacharya, research instructor in the Department of Neurology and Rehabilitation Medicine in UC’s College of Medicine. “Managing potential side effects and overcoming resistance to radiation are major challenges when treating brain metastases from lung cancer. This highlights the importance of new treatments which are less toxic and can improve the efficacy of radiation therapy, are less expensive, and can improve the quality of life in patients.”

Research focus

Bhattacharya and his colleagues at UC focused on AM-101, a synthetic analog in the class of benzodiazepine drugs first developed by James Cook, a medicinal chemist at the University of Wisconsin-Milwaukee. Prior to this study, AM-101’s effect in non-small cell lung cancer was unknown.

AM-101 is a particularly useful drug in the context of brain metastases in NSCLC, Bhattacharya said, as benzodiazepines are known to be able to pass through the blood-brain barrier that protects the brain from potential harmful invaders that can also block some drugs from reaching their target in the brain.

Research results

The team found AM-101 activated GABA(A) receptors located in the NSCLC cells and lung cancer brain metastatic cells. This activation triggers the “self-eating” process of autophagy where the cell recycles and degrades unwanted cellular parts.

Specifically, the study showed that activating GABA(A) receptors increases the expression and clustering of GABARAP and Nix (an autophagy receptor), which boosts the autophagy process in lung cancer cells. This enhanced “self-eating” process of autophagy makes lung cancer cells more sensitive to radiation treatment.

Using animal models of lung cancer brain metastases, the team found AM-101 makes radiation treatment more effective and significantly improves survival. Additionally, the drug was found to slow down the growth of the primary NSCLC cells and brain metastases.

In addition to making radiation more effective, adding AM-101 to radiation treatments could allow for lower radiation doses, which could reduce side effects and toxicity for patients, Bhattacharya said. The team is now working toward opening Phase 1 clinical trials testing the combination of AM-101 and radiation both in lung cancer within the lungs and lung cancer that has spread to the brain.

Bhattacharya began this research while working in the lab of former UC researchers Soma Sengupta and Daniel Pomeranz Krummel, who are now at the University of North Carolina at Chapel Hill. Bhattacharya credits their mentorship and the collaboration with other experts within UC and across multiple academic research institutions in the United States.

Bhattacharya also emphasizes the role of shared university research resources that helped the study move forward. He dedicates this work to his father, who died in 2021 while he was in the early phases of the research.

“The entire work, along with revision experiments, was done at the University of Cincinnati, and this reflects the strong collaborative effort between multiple teams. I am grateful to the Department of Neurology and Rehabilitation Medicine for the overall support in completion of this study,” he said. “My father’s passing motivated me to work harder to complete this project, as he had known about my research and wanted to see me succeed.”