Scientists have found a missing key that unlocks critical channels that allow for the flow of potassium ion in a process that is essential for life. A major barrier to the development of novel drugs targeting a host of diseases has been overcome by the discovery.
A research team from WEHI and La Trobe Institute of Molecular Sciences have identified the key to opening a gate that controls the currents of potassium ion across cell membranes. Nerve signals in the brain and nervous system are transmitted by on currents.
Dysregulation of ion channels has been implicated in a number of diseases, including cancer, neurological, cardiac and kidney disorders. It has proved difficult to exploit ion channels, which are considered to be important druggable targets.
A conceptual breakthrough in understanding how the channels are gated has been made by the research led by Dr. Jacqui Gulbis from WEHI and Professor Brian Smith from La Trobe University. The study was published in the journal Nature Communications.
It's myth-breaking.
Cells have tiny, gated, pores in their cell membranes that allow for controlled potassium flow in and out of them. When the channel opens, the electrical signals that are essential for life are sent across the membrane.
Dr. Gulbis has been studying ion channels for 25 years.
The electrical signaling that causes the heart to beat and allows nerve impulses and muscle contraction can be accomplished through onion channels. They set off cellular signaling pathways so that they are tightly controlled. This can go awry in some medical conditions. We didn't know how to fix it.
A previous discovery of the team has overturned a widely accepted theory that the channels need to widen to allow the ion to cross.
In a paper released last year, we showed that the channel continues to function even when rendered incapable of widening. We knew that the prevailing theory was incorrect, but only with the new paper that we begin to explain what is really happening.
The key is missing.
The research team discovered that the ion channel embedded in the cell membranes held the missing key that controls the flow of potassium ion.
We applied structural biology, using data collected at the Australian Synchrotron, and other biophysical methods, to show that specific fatty lipids from the membranes interact tightly with the channel to open a gate that allows potassium ion to pass through. She said that the answer was hiding in plain sight.
There is a physical gate, but it is not where others think it is. For decades, scientists believed there must be a widening of the channel in order for the ion to pass through the cell. We showed last year that this was not the case, as we demonstrated that potassium can shed some of its water molecule to pass through a narrow opening. Disproving the conventional understanding was the first step in providing an alternative explanation.
We identified the gate, described its nature, and showed how specific lipids engage with the channel to operate it in this new study. The gate is in a different place than was thought, and it operates by a subtler, and completely different, process. She said it was obvious once you saw it.
Dr. Gulbis said that the discoveries overturn our understanding of how channels work.
Professor Smith said it showed how dynamic the cell was.
The cell is often thought of as passive and inactive, but we have shown that the cell is dynamic and has a more active role in controlling signaling than we think.
Professor Smith said the team made the discovery using sophisticated computer simulations of the channels.
He said that they used millions of hours of high- performance computing to run mathematical simulations to make the discovery.
Drug discovery.
Professor Smith said the discovery should reignite the search for drugs that target ion channel deregulation.
Disorders of ion channels have been implicated in many conditions. Dysregulation of these channels has been implicated in the progression and spread of some cancers.
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 laboring under a folkloric conviction as to how these ion channels work. This new information on how potassium channels are controlled will open up new avenues and ideas for the rational discovery and design of new treatments.
More information: Ruitao Jin et al, Ion currents through Kir potassium channels are gated by anionic lipids, Nature Communications (2022). DOI: 10.1038/s41467-022-28148-4 Journal information: Nature Communications Citation: Missing 'key' could overcome drug discovery barrier (2022, January 26) retrieved 26 January 2022 from https://phys.org/news/2022-01-key-drug-discovery-barrier.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
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