La Trobe University: Missing key could overcome drug barrier

The study, published in Nature Communications, identifies the ‘key’ to opening a molecular gate controlling currents of potassium ions across cell membranes.

The dysregulation of ion channels has been implicated in the development, progression and spread of some cancers, as well as neurological, cardiac and kidney disorders including epilepsy and diabetes. While ion channels are widely considered to be important druggable targets, it has previously proven difficult to exploit them.

Co-lead researcher Professor Brian Smith from La Trobe University’s Institute for Molecular Science (LIMS) said, “the discovery overturns and redirects our basic understanding of how potassium channels work and will reignite the search for drugs that target ion channel deregulation to treat disease”.

Myth-busting

Dr Jacqui Gulbis from WEHI has been studying ion channels for around 25 years.

“Ion channels facilitate all cell biology,” Dr Gulbis said. “They set up the cellular environment and, as well as the electrical signalling that causes the heart to beat and allows nerve impulses and muscle contractions. They set off cellular signalling pathways, so conduction through these channels is tightly controlled. In some medical conditions, this goes awry. Until now, we didn’t know how to even start to fix this.

A previous discovery of the team had overturned a widely accepted theory that potassium channels must physically widen to allow ions to cross the membrane, Dr Gulbis said.

“In a paper released last year, we showed that the channel continues to function even when rendered incapable of physically widening. So, while we knew that the prevailing theory was incorrect, it is only with this new paper that we begin to explain what is really happening.”

The missing key

Dr Gulbis said the research team discovered that the cell membrane in which the ion channel is embedded held the missing ‘key’ that controls the flow of potassium ions.

“We applied structural biology, using data collected at the Australian Synchrotron, and other biophysical methods to show that specific fatty lipids from the membrane interact tightly with the channel to open a gate that allows potassium ions to pass through. The answer was hiding in plain sight,” she said.

In this new study we have identified the gate, described its nature, and showed how specific membrane lipids engage with the channel to operate it. Not only is the gate in a different place than previously thought, it operates by a subtler, and completely different, process. Once you see it, it’s obvious,” she said.

Professor Smith said it provided evidence of how dynamic the cell membrane was.

“The cell membrane is often thought of as inert or passive, but we have shown that it is actually incredibly dynamic, and lipids that are bound within the cell membrane have a much more active role in controlling proteins and signalling than is typically considered.”

“For more than 20 years the search for pharmaceuticals that can exploit ion channels to treat disease has been in hiatus, because drug companies were labouring under a folkloric conviction as to how these ion channels work. This new information on how potassium channels are controlled – or at least the nuts and bolts of it – will open up new avenues and ideas for the rational discovery and design of new treatments.”

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