Ion channels are important targets for drug development because they play a critical role in both health and sickness. Selectively targeting particular ion channels is still quite difficult, though. Researchers at RMIT University in Australia and Weill Cornell Medicine have shown that BK channels, a particular kind of ion channel, have distinctive side openings. Drug molecules might be able to selectively enter the channels thanks to these holes. This discovery may result in novel medications that target the BK channel to treat a variety of illnesses. It is described in a recent research that was published in Nature Chemical Biology.
Knowing BK Channels and Ion Channels
Many biological activities depend on the passage of charged molecules into and out of cells, which is controlled by ion channels, which are tunnel-like structures embedded in cell membranes. For example, BK channels regulate the flow of potassium ions, and genetic abnormalities in these channels have been associated with issues in several organ systems.
“It’s an exciting development that small molecules can now selectively access this important type of ion channel,” Weill Cornell Medicine professor of physiology and biophysics and co-senior author of the study Dr. Crina Nimigean stated.
Dr. Toby Allen, an Australian professor at RMIT University in Melbourne, is the other co-senior author of the research. During the study, Dr. Chen Fan, the lead author, worked as a postdoctoral research associate in the Department of Anesthesiology’s Nimigean Lab.
Investigating BK Channel Architectures
In addition to doing direct studies, Dr. Nimigean and her colleagues have been investigating the composition and operation of BK channels through studies on the more easily studied bacterial variant, MthK. It was recently shown that even in cases when structural imaging indicates that the pore’s entry is totally closed, a family of compounds that inhibit MthK and BK can successfully plug the MthK channel, or “pore.” These compounds are not acceptable as medications, but they are valuable as laboratory tools.
“We questioned how these compounds were able to enter since they wouldn’t have direct access to the pore in this closed state,” Dr. Nimigean stated.
The researchers used structural imaging techniques, tests with both normal and mutant MthK, and computer modelling of the interactions between the channel-blocking drugs and the MthK ion channel in Dr. Allen’s lab to answer this puzzle.
They found that the structure forms sizable apertures on its sides when MthK is in the closed state, allowing the MthK-blocking chemicals to enter the ion-conducting pore. Since these holes are located inside the cell membrane, the MthK-blocking substances must first pass through a small opening in the membrane in order to get to them.
From the structural data that is currently available, the researchers also noticed that BK channels have side-openings, or “fenestrations,” similar to those found in MthK channels.
Possibility of Development of Selective Drugs
Drugs that block or activate BK may be able to treat conditions like hypertension and epilepsy, according to scientists. Nevertheless, little is known about how modifications to the BK channel’s structure relate to the channel’s function, which contributes to the lack of a specific BK channel-modulating medication. Another issue is that medications that block BK channels also impact other ion channels because they usually target the potassium-conducting chute’s entrance, or the “pore,” which is similar to the pores of other ion channels. Such random interactions might cause the body to malfunction.
Dr. Nimigean stated, “Since these fenestrations are specific to BK-type channels, it is possible that future medications that target these sites will act as selective BK channel activators or blockers.”
In order to locate specific BK channel-modulating chemicals that may be turned into medications, she and her colleagues are organising follow-up BK channel research.
Reference: “Calcium-gated potassium channel blockade via membrane-facing fenestrations” by Chen Fan, Emelie Flood, Nattakan Sukomon, Shubhangi Agarwal, Toby W. Allen and Crina M. Nimigean, 31 August 2023, Nature Chemical Biology.
