Functional polarity of ATP1A3 small-molecule modulators

Determine whether candidate small molecules bind ATP1A3 as potentiators or inhibitors, and identify compounds that increase ATP1A3 pump turnover with sufficient selectivity over the ATP1A1 and ATP1A2 isoforms.

Background

CircuitATLAS nominated potentiation of the neuronal α3 Na+/K+-ATPase, ATP1A3, as a potential intervention for cortical hyperexcitability, and interneuron-restricted ATP1A3 expression reduced challenge-evoked beta- and gamma-band activity in vivo. The subsequent structure-guided campaign generated predicted binders and ranked binding sites according to the prior probability that occupancy would increase pump turnover.

The authors explicitly identify a remaining uncertainty: docking scores predict binding but cannot determine whether a compound will potentiate or inhibit ATP1A3. They therefore leave the issue to a functional thallium-flux assay using human ATP1A3, with ATP1A1 and ATP1A2 measured in parallel, followed by an ATPase Na+ dependence assay for compounds showing the intended activity.

References

The modelling also exposed the principal uncertainties: limited $\alpha$3 versus $\alpha$1 sequence divergence across most pockets, the small size of the available cavities, and most importantly the inability of docking alone to distinguish potentiators from inhibitors.

— CircuitATLAS: Agentic reasoning over a systems neuroscience knowledge graph for target discovery in circuitopathies  (2610.09643 - Ocana-Santero et al., 7 Oct 2026) in Section “Closing the loop from target nomination to experimental validation,” paragraph beginning “The campaign assembled”; Methods, subsection “Structure-guided small-molecule campaign”