Researchers have determined the first high-resolution structure of a brain protein linked to epilepsy, autism spectrum disorder and other neurological conditions, while also developing the first compounds capable of blocking its activity, offering a potential new avenue for neurological drug discovery.
Published in Nature Communications, the study focused on the neuronal protein NBCn2, a transporter that helps regulate acid-base balance within brain cells by moving sodium and carbonate ions across cell membranes. Although genetic variants affecting NBCn2 have previously been associated with epilepsy and autism, little has been known about its structure or function, limiting efforts to develop targeted therapies.
Scientists at the Icahn School of Medicine at Mount Sinai used cryo-electron microscopy to produce the first detailed structural images of NBCn2, revealing how the transporter binds and moves ions that help regulate neuronal excitability.
Using this structural information, the team designed and screened compounds capable of inhibiting NBCn2. Laboratory experiments in cultured neurons and mouse brain tissue showed that one of these compounds reduced electrical signalling between nerve cells, demonstrating that the transporter can be pharmacologically targeted.
The researchers also identified an unexpected mechanism by which NBCn2 binds sodium and carbonate ions. The binding arrangement differed from that seen in related transport proteins, suggesting opportunities to design drugs that selectively target NBCn2 while avoiding similar transporters.
The study combined cryo-electron microscopy with artificial intelligence-based structural prediction, computer modelling and virtual screening of millions of chemical compounds to identify potential inhibitors before testing them experimentally.
| Sign up to the ACNR email newsletter here |
The authors stress that the compounds are early-stage research tools rather than candidate medicines. Further work will be needed to improve their potency and selectivity and to evaluate their safety and effectiveness in animal models and human-derived systems before clinical development can be considered.
Nevertheless, the findings provide an important framework for investigating NBCn2 as a therapeutic target for epilepsy and other neurological disorders characterised by excessive neuronal activity. The researchers also believe the approach could accelerate the study of other previously understudied transporter proteins involved in diseases of the nervous system.
This news item has been summarised using AI and checked by humans before publication.
Sources
| Sign up for our online community for neurology specialists |
