Researchers have discovered how an ion channel in the brain’s neurons has a kind of ‘molecular memory’, which contributes to the formation and preservation of lifelong memories. The researchers have identified a specific part of the ion channel at which new drugs for certain genetic diseases could be targeted. The study, led from Linköping University in Sweden, has been published in Nature Communications.

One of the brain’s superpowers is its ability to learn from past experiences and form memories. These vital processes depend on the reshaping of connections between neurons in the brain. Nerve junctions, called synapses, are strengthened or weakened throughout life in such a way that the brain is, in a certain sense, constantly being reshaped at the cellular level. This phenomenon is called synaptic plasticity.

There are several processes contributing to synaptic plasticity in the nervous system. One of these processes has to do with a type of molecules called calcium ion channels, which have long been of interest to researchers at Linköping University (LiU).

“I want to uncover the secret lives of these ion channel molecules. Calcium ion channels have very important functions in the body – by opening and closing, they regulate, among other things, nerve-to-nerve signalling. But beyond that, these molecules also have a kind of memory of their own, and can remember previous nerve signals,” says Antonios Pantazis, associate professor at the Department of Biomedical and Clinical Sciences at LiU, who led the study.

The focus of this study was on a specific type of ion channel, the CaV2.1 channel, which is the most common calcium ion channel in the brain. The ion channel is located at the synapse, at the very end of the neuron. When an electrical signal passes through the neuron, the ion channel open, setting in motion a process leading to neurotransmitter being released towards the receiving neuron in the synapse. In this way, CaV2.1 channels are the gatekeepers of synaptic, neuron-to-neuron communication.

Prolonged electrical activity reduces the number of CaV2.1 channels that can open, resulting in less transmitter release, so the receiving neuron receives a weaker message. It is as if the channels can ‘remember’ previous signalling, and in doing so, make themselves unavailable to open by subsequent signals. How this works at the molecular level has been unknown to scientists until now.

The Linköping researchers have now discovered a mechanism for how the ion channel can ‘remember’. The channel is a large molecule made up of several interconnected parts, which can move relative to each other in response to electrical signals. They discovered that the ion channel can take almost 200 different shapes depending on the strength and duration of an electrical signal; it is a very complex molecular machine.

“We believe that during sustained electrical nerve signalling, an important part of the molecule disconnects from the channel gate, similar to the way the clutch in a car breaks the connection between the engine and the wheels. The ion channel can then no longer be opened. When hundreds of signals occur over long enough time, they can convert most channels into this ‘declutched memory state’ for several seconds,” says Antonios Pantazis.

If the ion channel can ‘remember’ for just a few seconds, how does it contribute to lifelong learning? This type of collective memory in the ion channels can accumulate over time and reduce the communication between two neurons. This then leads to changes in the receiving neuron, lasting for hours or days. Eventually, it results in much longer-lived changes in the brain, such as the elimination of weakened synapses.

“In this way, a ‘memory’ that lasts for a few seconds in a single molecule can make a small contribution to a person’s memory that lasts for a lifetime,” says Antonios Pantazis.

Increased knowledge of how these calcium ion channels work can in the long term contribute to the treatment of certain diseases. There are many variants of the gene that produces the CaV2.1 channel, CACNA1A, that are linked to rare but serious neurological diseases, that often run in families. To develop drugs against these, it helps to know which part of the large ion channel you want to affect and in what way its activity should be changed.

“Our work pinpoints which part of the protein should be targeted when developing new drugs,” says Antonios Pantazis.

The research has been funded by the Swedish Research Council, the Linköping University Wallenberg Centre for Molecular Medicine, the Swedish Brain Foundation, the Swedish Heart-Lung Foundation, the Lions Research Fund for Public Diseases and the NIH.

Article: A rich conformational palette underlies human CaV2.1-channel availability, Kaiqian Wang, Michelle Nilsson, Marina Angelini, Riccardo Olcese, Fredrik Elinder and Antonios Pantazis, (2025), Nature Communications, published on 23 April 2025, doi: https://doi.org/10.1038/s41467-025-58884-2