Prediction of possible new drug binding site for ATP-sensitive potassium channel inhibition: bupropion's modulation of hippocampal CA1 neuron excitability.

Objective: Bupropion, a norepinephrine-dopamine reuptake inhibitor, is widely used as an antidepressant and smoking cessation aid. At high doses, it also inhibits pancreatic β-cell ATP-sensitive potassium (KATP) channels, inducing insulin secretion. KATP channels are also expressed in the brain, and their gain-of-function mutations cause neurological disorders such as developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). This study investigates bupropion's effects on KATP channels in mouse hippocampal CA1 pyramidal neurons.

Methods: The effects of bupropion on neuronal activity were examined in mouse hippocampal CA1 neurons using electrophysiological techniques. Specifically, whole-cell patch-clamp recordings were performed to measure changes in action potential firing frequency and membrane potential in response to bupropion application. To investigate the potential binding mechanism of bupropion to the KATP channel complex, AlphaFold3, an artificial intelligence-based protein structure prediction tool, was utilized.

Results: Electrophysiology revealed that bupropion significantly increased action potential firing frequency and altered membrane potential. AlphaFold3-predicted bupropion binding poses within sulfonylurea receptor 1 's transmembrane domain 0 highlighted key interactions. These structural predictions provide a plausible molecular basis for bupropion's observed electrophysiological effects.

Conclusion: These findings suggest bupropion's potential as a therapeutic strategy for DEND syndrome's neurological manifestations. Further investigation into the precise mechanisms and clinical applicability of these findings is warranted.