Photomodulation of Kv Channel Activity

Voltage-gated potassium (Kv) channels shape action potentials, with their activity dependent on anionic lipids and modulated by membrane tension. However, the mechanism by which lipids regulate channel gating is not entirely clear. Cryo-electron microscopy studies suggest that in the down state-- typically associated with the inactive channel--arginines of the voltage sensor interact with lipid phosphates, pulling them upward and locally thinning the membrane by [~]5 [A]. This thinning is absent in the up state of the sensor, which is typically associated with the active channel. To test whether membrane thickness influences gating, we reconstituted Aeropyrum pernix Kv (KvAP) channels into planar lipid bilayers containing photoswitchable lipids. Blue light increased membrane thickness and KvAP activity, while UV light reversed these effects. Our results indicate that membrane thickening disrupts voltage sensor-lipid phosphate interactions, lowering the activation barrier for the up-movement of the voltage sensor and thus, channel opening. The resulting leftward shift in the current-voltage relationship demonstrates a light-driven approach to modulating Kv channel activity, with potential applications in neuronal excitability control. SignificanceVoltage-gated Kv channels respond to membrane voltage in a manner influenced by lipid composition and membrane tension. In the inactive state, voltage-sensing arginines interact with lipid phosphates, and when these interactions are strained--such as by membrane thickening or possibly by membrane tension--less voltage is required for channel opening. We demonstrate this interdependence by showing that a light-triggered increase in membrane thickness reversibly enhances Kv channel activity, directly linking membrane mechanics to voltage sensing. This work also establishes a light-based strategy for spatially precise Kv channel modulation.