UChicago Medicine research reveals intriguing theory on hERG potassium channel function that could help improve heart care
March 30, 2021
In a discovery that could help to more easily develop medications that are safe for the heart, researchers at the University of Chicago Medicine are shedding light on the function of a potassium ion channel that plays a key role in regulating how the heart beats. The research could also eventually lead to treatments for patients with inherited conditions that cause life-threatening arrhythmias, such as long QT-syndrome.
Using computation and experimental analysis, the team has conducted one of the first systematic probes of the mechanism and pathway that causes the hERG potassium channel to inactivate. The latter is an auto-inhibitory mechanism that helps control against runaway signaling in ion channels.
“Our research revealed the channel might adopt an unusual asymmetrical, constricted-like conformation of the narrow selectivity filter when inactivated,” said Benoît Roux, PhD, the Amgen Professor of Biochemistry and Molecular Biology and senior author of the study published in Science Advances. “This is definitely intriguing and has not yet been seen in experimental structures of hERG.”
Similar in appearance to a pore, an ion channel is a protein located in a cell’s membrane that allows specific electrically charged ions to pass through the membrane. The channels conduct ions when they are open, and block them when they are closed or inactivated. Key to the heart’s function is the conduction of potassium, sodium and calcium ions through selective channels.
In heart cells, the hERG potassium channel helps orchestrate the electrical signals that govern the strength and rhythm of our beating hearts. In particular, the rapid passage of potassium ions through the hERG channel plays a critical role in repolarizing cardiac cells and allowing them to return to their basic resting state after every heart contraction.
For decades, researchers have struggled to understand exactly how the hERG potassium channel opens and closes, and most importantly, how it inactivates. These channels present a unique challenge to pharmaceutical developers because they can bind to a variety of different molecules, meaning drug molecules never intended to affect the heart can find their way to a cardiac hERG channel and block the cell’s ability to correctly conduct electrical signals. Even a small increase in inactivated hERG channels can seriously destabilize the delicate electrical balance of the heart and cause dangerous arrhythmias.
The most famous hERG conduction-blocking incident involved the antihistamine Seldane in the 1990s. The drug, terfenadine, was found to block the hERG channel and linked to several deaths. Seldane was pulled from the market in 1997, and pharmaceutical companies have since invested millions on screening new medications to ensure they won’t block the hERG channel.
“Understanding hERG’s activation and inactivation mechanisms holds the key to new and improved pharmacological compounds relevant to cardiac physiology,” said Eduardo Perozo, PhD, a professor of biochemistry and molecular biology who investigates the molecular structures of ion channels and other fundamental membrane proteins.
Eduardo added that because hERG-promiscuous drug interactions are directly related to the inactivated conformation of the channel, understanding how the hERG potassium channel inactivates could also contribute to treatments for a variety of arrhythmias and other cardiac electrical malfunctions.
The binding of small drug molecules to protein is best understood and rationalized on the basis of atomic structures. But no experimental structure of a hERG channel in the inactivated state is currently available. Using physics-based molecular dynamics simulations and high-performance computing resources, including UChicago’s Beagle supercomputer, the team found that inactivated hERG might be associated with a novel asymmetrical pinched-like conformation of the selectivity filter, the region of the channel that interacts with the ions. Additional experiments were shown to support this hypothesis.
Roux, a pioneer in cell membrane protein research that uses molecular dynamics and atomic models to better understand and predict the outcome of experiments, said the finding provides a broad paradigm to consider across a wide range of potassium channels.
The research builds off of a discovery made by Perozo’s team in 2010 that revealed the atomic structure of an inactivated potassium channel with the intracellular gate that controls ion flow open. Perozo’s groundbreaking finding used X-ray crystallography and a prokaryotic potassium channel belonging to the soil bacterium Streptomyces lividans to provide a framework for further potassium channel research.
The team is planning additional study of how specific drug molecules bind to the hERG channel in a C-type inactivated state to shed new light on how small molecules could be designed to avoid interfering with hERG channel function.
“Mechanism of C-type inactivation in the hERG potassium channel” was published January 29, 2021 in Science Advances. Additional authors are Jing Li of the University of Mississippi and Rong Shen and Bharat Reddy of the University of Chicago.