A Voltage- to Ligand- Gated Switch in Voltage-Gated Potassium Channels

To open voltage-gated ion channels (VGIC), the changes of membrane potential, usually depolarization, is prerequisite. In contrast, ligand-gated ion channels (LGIC) open when ligands bind. VGIC often stay in the close state under hyperpolarize membrane potentials. Small chemical ligands have been found to be able to allosterically modulate VGIC, but none of them can open VGIC in spite of membrane potential. Here, we report a cysteine is a ‘voltage- to ligand- gated’ switch for KCNQ2 channel. Substitutions with alanine (A) or other smaller volume amino acids in this position endow a ligand-gating to KCNQ2 channel in a measurable range of membrane potential. Under constant −120 mV or even lower membrane potentials, the mutant channels can be opened by small chemical ligands, such as ztz240 and ZnPy . Whereas, the wild type channel kept in close under the identical conditions. Further mechanism investigations revealed that the volumn rather than other properties in this position is essential for the ligand induced opening, inferring that this position may function as a baffle plate that restricts the upward movement of the S4 segment. Our study reports a ligand-gated opening of KCNQ2 channel for the first time. The identification of the ‘voltage- to ligand-gated’ switch in KCNQ2 channels breaks through the traditional barrier between VGIC and LGIC.