PIP2 controls voltage-sensor movement and pore opening of Kv channels through the S4-S5 linker

Voltage-gated K+ (Kv) channels couple the movement of a voltage sensor to the channel gate(s) via a helical intracellular region, the S4-S5 linker. A number of studies link voltage sensitivity to interactions of S4 charges with membrane phospholipids in the outer leaflet of the bilayer. Although the phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) in the inner membrane leaflet has emerged as a universal activator of ion channels, no such role has been established for mammalian Kv channels. Here we show that PIP2 depletion induced two kinetically distinct effects on Kv channels: an increase in voltage sensitivity and a concomitant decrease in current amplitude. These effects are reversible, exhibiting distinct molecular determinants and sensitivities to PIP2. Gating current measurements revealed that PIP2 constrains the movement of the sensor through interactions with the S4-S5 linker. Thus, PIP2 controls both the movement of the voltage sensor and the stability of the open pore through interactions with the linker that connects them.