Commonly used anesthetics can restore function of epilepsy-related ion channels

Mutations in certain ion channels cause hard-to-treat epilepsy, study published in the journal Nature Now, researchers at Linköping University and Weill Cornell Medicine have found that the commonly used anesthetic propofol can restore the function of this ion channel, opening up opportunities for the development of drugs to treat the disease in the long term.

A drug called propofol is often used to anesthetize patients for medical procedures, but in some people it can cause a slow heart rate and extremely slow pulse because it affects an ion channel called HCN1.

“The HCN1 ion channel is also known as the pacemaker channel because it determines the rhythm of the heart and controls certain nerve cells in the brain with rhythmic behavior,” says Peter Larsson, professor of molecular neurophysiology at Linköping University and one of the researchers of the study published in 2010. Nature.

There are several known mutations in the HCN1 ion channel that cause epilepsy in childhood. These mutations can cause the ion channel to open too much, releasing more ions than necessary and leading to uncontrolled neuronal signaling. Epilepsy caused by mutations in the HCN1 ion channel is often difficult to treat with currently available medications.

Because propofol reduces the activity of HCN1, researchers at Weill Cornell Medicine and Linköping University sought to understand more about how the drug interacts with and blocks the ion channel. In the process, they made an unexpected discovery.

“When we used propofol on the mutant ion channel, we found that it actually restored function, making the mutated channel function almost identically to a normal channel. We've never seen this happen with other ion channels, so it's really surprising that we were able to use propofol to restore function to the ion channel.”

Peter Larsson, Professor of Molecular Neurophysiology, Linköping University

This discovery gave the researchers the idea that this new knowledge could be useful in the development of new drugs: by modifying propofol to eliminate its sedative effects and restoring only the function of the mutant HCN1 ion channel, it might be possible to develop a new anti-epileptic drug. Conversely, it might be possible to develop an improved version of propofol for use in anesthesia that does not have the side effects that the drug currently has on heart rhythm.

Developing improved forms of the drug requires understanding exactly how propofol binds to HCN1 and how its various effects occur. In the current study, researchers have made a breakthrough in this regard. A team of researchers from Weill Cornell Medicine used cryo-electron microscopy, a method that allows them to see individual atoms within molecules. They managed to get a clear picture of how propofol binds to the ion channel.

“The cryo-electron microscopy structure reveals that propofol binds to a mechanistic hotspot in the HCN1 channel, which is critical for coupling the voltage sensor region with the channel gate. Mutant channels in this region become unresponsive to voltage stimuli and have been associated with epilepsy. Propofol binding may act as glue to repair this interface in mutant channels and restore proper function, making it a useful pharmacological tool to treat these diseases,” said Kurina Nimidjian, professor of physiology and biophysics in the Department of Anesthesiology at Weill Cornell Medical College.

The ion channel itself consists of two parts: one part senses the voltage across the cell membrane and is called the voltage sensor, and the other part forms the channel through which ions pass. The channel has a kind of gate that controls whether the channel is open or closed.

“Propofol seems to close the ion channel HCN1 more than necessary. In our study, we found that propofol makes the closed shape of the channel more stable. This effect of propofol may explain why the heart rate slows in some patients, because the HCN1 channels no longer stimulate the heart as much. By the same effect, propofol restores the function of mutated HCN1 channels that cause epilepsy, because these mutations cause the channel to be too open,” says Peter Larsson.

Propofol sits between the voltage sensor of the ion channel and the opening of the channel and appears to improve the intercommunication between the two parts. This part of the ion channel has received little attention in previous studies, and this study provides important knowledge about the function of ion channels.

This research was funded by the National Institutes of Health (NIH) and others.

Fact: How ion channels control nerve signaling

Nerve signals are electrical impulses that occur when there is a sudden change in voltage, or the difference between the charge inside a nerve cell and the charge of the external environment.

When different ion channels open and close, releasing charged ions through the cell membrane, a change in voltage occurs.

When this happens incorrectly, the nerves can send signals too easily, which can have serious consequences, such as irregular heartbeats or epileptic seizures.