Dual Effect of PIP2 on Shaker K+ Channels

Phosphatidylinositol-(4,5)-bisphosphate (PIP2) is a phospholipid of the plasma membrane that has been shown to be a key regulator of several ion channels. Functional studies and more recently structural studies of Kir channels have revealed the major impact of PIP2 on the open state stabilization. A similar effect of PIP2 on the delayed rectifiers Kv7.1 and Kv11.1, two voltage-gated K+ channels, has been suggested, but the molecular mechanism remains elusive. By combining giant-patch ionic and gating current recordings in COS-7 cells, and voltage-clamp fluorimetry in Xenopus Oocytes, both heterologously expressing the voltage-dependent Shaker channel, we show that PIP2 exerts (1) a gain-of-function effect on the maximal current amplitude, consistent with a stabilization of the open state and (2) a loss-of-function effect by positive-shifting the activation voltage dependence, most likely through a direct effect on the voltage sensor movement, as illustrated by Molecular Dynamics simulations.