Designer voltage-gated anion channels suppress neuronal firing

Voltage-gated ion channels – transmembrane proteins that control the flow of ions in response to environmental stimuli – are essential for the function of excitable cells such as muscles and neurons. Designing such proteins from scratch could offer new tools for modulating cellular activity, but this is challenging because it requires precise, stimulus-induced confirmatory changes. In an article published in CellZhou et al. report the de novo design of tunable voltage-gated anion channels, which they use to suppress neuronal firing.

The authors constructed their anion channels through iterative rounds of computational design and experimental validation. First, they designed the pentameric structure of their ion channels and optimized them for membrane localization. They then introduced arginine residue into the pores to create a positively charged environment that attracts anions. As predicted by AlphaFold and confirmed by cryo-electron microscopy and molecular dynamics analysis, these arginine side chains undergo conformational changes in response to membrane potentials, thereby regulating pore opening and acting as both a voltage sensor and selectivity filter.