New Possibilities for Ion Channel-Targeting Drugs Unveiled Through Groundbreaking Discovery

Researchers have made an innovative discovery, finding side openings in BK ion channels. This finding may offer a new approach to creating specialized drugs to target these channels, offering a solution to a significant difficulty in ion channel drug development.

Ion channels play a vital role in health and disease, and as such, are crucial targets for drug development. Targeting specific ion channels selectively, however, has always been a major challenge. Now, researchers from Weill Cornell Medicine and RMIT University in Australia have discovered unique side openings in BK channels, a type of ion channel. They propose that these openings could provide a way for drug molecules to selectively access the channels. The researchers' findings, published in a recent Nature Chemical Biology paper, could lead to the creation of novel drugs targetting the BK channel to treat a variety of diseases.

Ion channels are tunnels embedded in cell membranes that regulate the flow of charged molecules into and out of cells, which is critical for many biological processes. For instance, BK channels facilitate the flow of potassium ions and inherited mutations in these channels have been associated with problems in multiple organ systems.

Dr. Crina Nimigean, professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine and co-senior author of the study, said, “The discovery of a location where small molecules can selectively access this essential type of ion channel is an exciting advancement.”

The other co-senior author of the study is Dr. Toby Allen, a professor at RMIT University in Melbourne, Australia. The paper's first author, Dr. Chen Fan, was a postdoctoral research associate in the Nimigean Lab in the Department of Anesthesiology during the study.

Dr. Nimigean and her team have been studying the structure and function of BK channels, using both direct methods and experiments on an easier-to-study bacterial version called MthK. Notably, they observed that a family of MthK- and BK-blocking compounds can access and effectively block the MthK channel, even when imaging shows that the entrance to the channel is completely closed.

To unravel this mystery, the team used structural imaging methods, performed experiments with normal and mutated MthK, and employed computer modeling of the interactions between the channel-blocking compounds and the MthK ion channel in Dr. Allen’s laboratory.

The researchers found that when MthK is in a closed state, large side openings develop through which the MthK-blocking compounds can access the ion-conducting pore. This requires the MthK-blocking compounds to travel a short distance into the membrane before reaching them. The team also identified similar side openings, or "fenestrations," in BK channels.

Scientists believe that drugs that block or activate BK channels could be beneficial for treating disorders like epilepsy and hypertension. As yet, no selective BK channel-modulating drug exists, partly due to a lack of understanding of how changes in the BK channel structure affect function. Another issue is that drugs affecting BK channels can intersect with other ion channels because they typically target the entrance to the potassium-conducting chute or "pore", which is similar to the pores of other types of ion channels. Such non-selective interactions could cause extensive problems in the body.

“These fenestrations are unique to BK-type channels, which implies that future drugs targeting these sites could function as selective BK channel blockers or activators,” said Dr. Nimigean.

Dr. Nimigean and her team have plans for further experiments on BK channels, aiming to use their findings to discover selective BK channel-modulating compounds that could potentially be developed into drugs.

The findings are detailed in the study titled “Calcium-gated potassium channel blockade via membrane-facing fenestrations” authored by Chen Fan, Emelie Flood, Nattakan Sukomon, Shubhangi Agarwal, Toby W. Allen and Crina M. Nimigean, which was published on 31 August 2023, in Nature Chemical Biology.