Fast-switching pH-responsive biomimetic ion channels with bidirectional gating control

Acid-sensing ion channels (ASICs) achieve millisecond-gated control over ion permeation through global conformational shifts induced by their acidic pockets. Inspired by this mechanism, we developed a pH-responsive artificial transmembrane transport system by biomimetically reconstructing an acidic pocket domain through the incorporation of a carboxyl-rich cluster into a pillararene-cyclodextrin hybrid scaffold. Transmembrane transport experiments confirmed that this artificial system forms stable, cation-selective ion channels, with its carboxyl groups acting as pH sensors to mediate reversible switching between ON and OFF transport states. Crucially, the gating mechanism is driven by pH-triggered <i>in situ</i> conformational changes, mirroring that of natural ASICs. Stopped-flow experiments further demonstrated that this biomimetic system exhibits millisecond-timescale gating kinetics under pH modulation, achieving response rates comparable to those of natural ion channels.