Missing ‘key’ could overcome drug discovery hurdle
Scientists have discovered a missing “key” that unlocks critical channels responsible for moving potassium ions across cell membranes in a process essential for life. This discovery overcomes a major obstacle to the development of new drugs targeting a multitude of diseases, including certain cancers.
a missing “key” that unlocks the door to control the
conduction of potassium ions through cell membranes.
The WEHI research team and La Trobe Institute for Molecular Sciences (LIMS) have identified the “key” to open a molecular gate controlling the currents of potassium ions through cell membranes. Ion currents transmit nerve signals in the brain and nervous system, regulate heart rate, and facilitate a host of critical cellular and tissue processes.
Dysregulation of ion channels has been implicated in the development, progression, and spread of certain cancers, as well as neurological, heart, and kidney disorders, including epilepsy and Diabetes. Unfortunately, while ion channels are widely regarded as important drug targets, exploiting them has proven difficult.
The research, conducted by Dr. Jacqui Gulbis of WEHme and Professor Brian Smith of La Trobe University, solves a decades-old problem, making a conceptual breakthrough in understanding how channels are closed. The study was published in the journal Nature Communication, with first authors Dr Ruitao Jin and Sitong He of LIMS and Dr Katrina Black of WEHI.
In one look
- WEHI and LIMS researchers have identified a missing “key” that unlocks the door to control the conduction of potassium ions across cell membranes.
- Dysregulation of these ion channels has been implicated in the development, progression, and spread of certain cancers, as well as neurological, heart, and kidney disorders, including epilepsy and diabetes.
- The research discovery could jump-start the search for drugs that target ion channel dysfunction, to treat a host of diseases.
Busting the Myths
Potassium ion channels are tiny closed pores in cell membranes that allow a controlled flow of potassium into and out of cells. Potassium conduction is regulated by an internal gate in the channel; when it opens, potassium flows through the membrane, transmitting electrical signals essential for life.
Dr. Gulbis has been studying ion channels for about 25 years.
“Ion channels facilitate all cell biology,” Dr. Gulbis said. “They set up the cellular environment and, as well as the electrical signaling that makes the heart beat and allows nerve impulses and muscle contractions. They trigger cell signaling pathways, so conduction through these channels is tightly controlled. In some medical conditions, this goes wrong. Until now, we didn’t even know how to start solving this problem.
A previous discovery by the team overturned a widely accepted theory that potassium channels must physically widen to allow ions to cross the membrane, Dr Gulbis said.
“In a paper published last year, we showed that the channel continues to function even when rendered unable to physically widen. So while we knew the prevailing theory was incorrect, it is only ‘with this new article we begin to explain what is really going on.
The missing key
Dr Gulbis said the research team discovered that the cell membrane in which the ion channel is embedded contains 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 in the membrane interact tightly with the channel to open a gate that allows potassium ions to pass. The answer was hiding in plain sight,” she said.
“There is a physical gate, but it is not located where others have thought. Potassium ions have their electrical charges protected by a ‘mantle’ of water molecules, and for decades the scientists believed that there must be a widening of the channel to allow ions, widened by this tightly held mantle of water molecules, to cross the cell membrane Last year we showed that this was not the case, by demonstrating that potassium can lose some of its water molecules to pass through a very narrow opening. Disproving the conventional understanding was the first step in providing an alternative explanation of how potassium flows through membranes is controlled.
In this new study, we identified the gate, described its nature, and showed how specific membrane lipids engage with the channel to make it work. Not only is the door in a different place than previously thought, but it works through a more subtle and completely different process. Once you see it, it’s obvious,” she said.
Dr Gulbis said that together these discoveries upend and reorient our basic understanding of how potassium channels work.
Professor Smith said this provided evidence for cell membrane dynamics.
“The cell membrane is often thought of as inert or passive, but we have shown that it is actually incredibly dynamic, and cell membrane-bound lipids have a much more active role in controlling proteins and signaling than this. which is generally considered.”
Professor Smith said the team made the discovery using sophisticated computer simulations of the channels using National Computational Infrastructure (NCI) Australia and the University of Melbourne’s LIEF HPC-GPGPU Facility. .
“We used millions of hours of high-performance computing to run mathematical simulations to make this discovery, using the kind of hardware typically used for gaming or bitcoin mining,” he said.
Professor Smith said the discovery should jump-start the search for drugs that target dysregulated ion channels to treat disease.
“Ion channel disorders – channelopathies – have been implicated in many conditions, including heart disease, neurological and nervous disorders, kidney disease, and diabetes. Dysregulation of these channels has also been implicated in the progression and spread of certain cancers because it promotes the tumor microenvironment,” said Dr. Gulbis.
“For more than 20 years, the search for pharmaceuticals capable of harnessing ion channels to treat disease has been halted, as pharmaceutical companies have been working under a folkloric belief about how these ion channels work. This new information about how potassium channels are controlled – or at least the workings of them – will open up new avenues and ideas for the rational discovery and design of new treatments.
The research was supported by the Australian National Computational Infrastructure, the Australian Synchrotron, the Australian Research Training Fellowships, the Wellcome Trust and the Victorian Government.