More current with less calcium: Computational models help solve longstanding ion channel evolution mystery

In the early 1980s, scientists observed an anomaly. Embedded within cell membranes, they identified ion channels with extraordinarily high conductance. These so-called "BK" (Big K, or Big Potassium) channels had roughly 10 times the unitary conductance (i.e., conductance per individual channel molecule) of other potassium channels, enabling much more efficient, rapid transport of potassium ions. And while later structural characterization explained how this happened, no one could understand why. That is, until now.

Published in Communications Biology, new research from the Okinawa Institute of Science and Technology (OIST) has shed light on the evolutionary origins of these powerful potassium conduits. Through molecular simulation and evolutionary modeling, the researchers explored neuronal BK channel conductance across species and identified its effect on spike timing as a probable evolutionary pressure in the channel's development.

Erik De Schutter, head of OIST's Computational Neuroscience Unit and an author of the study, comments, "BK channels are widely present across different neurons and known to be essential in regulating cell firing, the process in which electrical signals (spikes) coordinate communication between brain cells.

"Despite their importance, no one really knew why we had developed these extraordinarily high-conductance channels. Our work provides a possible answer to this longstanding mystery."

The importance of BK channels

Achieving even the simplest of tasks, like reading this sentence, relies on a complex jumble of neurons. Different cells and areas within the brain are involved in different data storage and processing tasks, and the whole system depends on careful intercellular communication.

Electrical signals are responsible for coordinating this communication, triggering the release of chemical neurotransmitters. These electrical signals are generated by charge changes at the cell membrane due to the movement of positively charged ions, which move through dedicated ion channels.

While many ion channels exist, BK channels are particularly interesting to neuroscientists because of their high conductance, a measure that indicates how easily ions can pass through the channel. Across the animal kingdom, BK channels show significantly higher unitary conductance than other types of potassium ion channels, sometimes 10–20 times as high.

"However, channel conductance isn't universal across species," adds De Schutter. "It's extremely high in mammals or birds compared to invertebrates. We wanted to understand why."

To explore these differences, De Schutter and his lab members enlisted the help of evolutionary biologists Thomas Bourguignon and Dr. Simon Hellemans of OIST's Evolutionary Genomics Unit. Using genomic data and literature reports, they mapped BK channels and their conductance across species, identifying a clear trend. The closer a species was to mammals on the evolutionary tree, the higher its BK conductance seemed to be.

Taking STEPS forward

Using a molecular simulation program called STEPS, the team then modeled individual ion channels.

"BK channels are calcium-activated, binding four calcium ions to fully open," explains De Schutter. "Using our STEPS program, we could model BK channels with differing conductance levels, taking into account calcium concentrations too."

Their models suggested that calcium removal was a key limiting factor in BK channel activation. In species with lower BK unitary conductance, many more channels had to be activated to achieve the same overall conductance. But activation requires calcium, and as calcium ions became bound to each channel, the amount of free calcium available dropped, effectively causing competition between channels. This was not an issue for channels with higher unitary conductance, as found in mammals and birds.

The team then used another model to examine the effects of conductance on spike timing—the precise moments when neurons produce electrical spikes. Such spikes are essential across many advanced brain functions, such as motor control, memory retention or sensory processing. At lower BK unitary conductance, spike timing was more variable.

"We suspect spike timing may be a critical evolutionary pressure behind the increase in conductance across channels for mammals compared to invertebrates," explains De Schutter. "As these animals evolved more complex motor function, precise, submillisecond spike timing became essential in achieving a wide variety of tasks."

As with all computational models, the study comes with limitations. The models present simplified, theoretical approximations of cells, focusing on just one type of neuron—the Purkinje cell. However, the researchers hope that the study can act as inspiration for others to further investigate these channels.

"BK channels are widespread across different cell types and involved in other functions too, such as muscle contraction," says De Schutter. "I hope that our study provides insights useful not only for neuroscientists but also for other cell and evolutionary biologists."