Genetic variants in a protein called NBCn2 have been tied to epilepsy and autism spectrum disorder for years. Until three weeks ago, nobody had seen what the protein looked like, and nobody had a compound that could switch it off.
Researchers at the Icahn School of Medicine at Mount Sinai now have both, and their first inhibitors of the protein are already reducing neuronal activity in the dish. Their work, published in Nature Communications on July 22, reports the first high-resolution structure of NBCn2, along with a series of compounds that inhibit it.
The structure came with a surprise that may matter more than the compounds do.
The Transporter That Kept the Brain’s pH and Nobody’s Attention
NBCn2, cataloged as SLC4A10 and a member of the SLC4 solute carrier family, is a sodium-dependent bicarbonate transporter. Its job is acid extrusion: moving sodium and carbonate ions across membranes to regulate acidity inside brain cells.
That sounds like housekeeping, but intracellular pH directly influences how readily neurons fire. Mutations in NBCn2 cause severe neurodevelopmental disorders in humans, and knockout studies have suggested that its role in regulating neuronal excitability could hold therapeutic potential for seizure disorders.
The obstacle was practical. As the authors put it, NBCn2’s molecular mechanisms remained largely unknown, and few tool compounds were available to probe its role in health and disease. Without knowing a protein’s shape or what it binds to and where it moves, designing a molecule to block it is guesswork.
Cryo-EM, Computation and a Compound Series
The team used cryo-electron microscopy to capture detailed structural images of the transporter, revealing how it binds and moves the ions that shape neuronal excitability, as the Mount Sinai announcement describes.
They then paired that structural data with computational docking and molecular simulation to run structure-based drug discovery, narrowing a large chemical space to candidates worth synthesizing and testing.
The screen produced a compound series that inhibits NBCn2-mediated transport. In primary neuronal culture and in brain slices, the compounds reduced neuronal activity, which is the direction you would want from a candidate for disorders of excessive firing. The team then went back to cryo-EM to characterize the mechanism of inhibition.
The Binding Surprise That Matters for Drug Design
The structural detail with the longest reach is not the compound but the mechanism.
NBCn2 binds sodium and carbonate in an arrangement that differs from related proteins in the same transporter family. Closely related transporters, in other words, may operate in distinct ways.
“One surprising finding was that NBCn2 uses a substrate binding mechanism we had not seen before in related proteins,” said Shifan Yang, first author and a senior scientist in the Department of Genetics and Genomic Sciences. “That difference may ultimately help all scientists design more selective drugs in the future.”
Selectivity is the central problem in drug design for transporter families. Compounds that hit the intended target plus three of its cousins tend to produce side effects that kill development programs. A genuinely different binding site is an opening for molecules that engage NBCn2 and leave its relatives alone.
Why “Not Drugs” Is the Operative Phrase
The team is unusually blunt about how early this is.
“These compounds are not drugs,” co-corresponding author Avner Schlessinger, professor of pharmacological sciences and director of the Small Molecule AI Drug Discovery Center at Icahn Mount Sinai, said in the release. The authors characterize them as early-stage research tools not ready for use in patients.
Several gaps are worth naming. Reducing neuronal activity in cultured cells and brain slices is not equivalent to reducing seizures in a living animal, and no seizure model results are reported. The compounds have not been reported to cross the blood-brain barrier, nor have they been assessed for toxicity or behavior in a whole organism. And blocking a pH regulator across the brain raises obvious questions about what else it would affect.
Roughly a third of people with epilepsy do not achieve seizure control on existing medications, which is why new mechanisms attract interest. But this is the first step of a process that typically runs a decade and usually fails. As one clinical neurology outlet framed it, the value here is a framework for studying the protein, not a therapy. Anyone currently managing epilepsy should stay on their prescribed regimen and discuss changes only with their neurologist.
Key Questions Answered
What is NBCn2?
A sodium-dependent bicarbonate transporter, also called SLC4A10, that regulates acid-base balance inside brain cells and influences how readily neurons fire.
What did the researchers accomplish?
They produced the first high-resolution structure of the protein using cryo-electron microscopy and used it to design the first compounds that inhibit its activity.
Did the compounds work?
They reduced neuronal activity in primary culture and brain slices. No seizure model results were reported.
Why is the binding mechanism significant?
NBCn2 binds sodium and carbonate differently from related transporters, suggesting that drugs could be designed to target it specifically without affecting its relatives.
Are these compounds close to becoming medicines?
No. The researchers explicitly describe them as early-stage research tools not yet ready for use in patients.
Who could eventually benefit?
Potentially, people with epilepsy and other conditions involving excessive neuronal activity, though no therapeutic claim is supported by this study.