PIP₂-dependent coupling of voltage sensor and pore domains in K_v7.2 channel

Phosphatidylinositol-4,5-bisphosphate (PIP₂) is a signaling lipid which regulates voltage-gated K_v7/KCNQ potassium channels. Altered PIP₂ sensitivity of neuronal K_v7.2 channel is involved in KCNQ2 epileptic encephalopathy. However, the molecular action of PIP₂ on K_v7.2 gating remains largely elusive. Here, we use molecular dynamics simulations and electrophysiology to characterize PIP₂ binding sites in a human K_v7.2 channel. In the closed state, PIP₂ localizes to the periphery of the voltage-sensing domain (VSD). In the open state, PIP₂ binds to 4 distinct interfaces formed by the cytoplasmic ends of the VSD, the gate, intracellular helices A and B and their linkers. PIP₂ binding induces bilayer-interacting conformation of helices A and B and the correlated motion of the VSD and the pore domain, whereas charge-neutralizing mutations block this coupling and reduce PIP₂ sensitivity of K_v7.2 channels by disrupting PIP₂ binding. These findings reveal the allosteric role of PIP₂ in K_v7.2 channel activation.