Molecular dynamics simulations and electrophysiology reveal the specific binding sites and allosteric role of PIP2 in the voltage-dependent activation of neuronal Kv7.2 channels.
Abstract Phosphatidylinositol-4,5-bisphosphate (PIP 2 ) is a signaling lipid which regulates voltage-gated K v 7/ KCNQ potassium channels. Altered PIP 2 sensitivity of neuronal K v 7.2 channel is involved in KCNQ2 epileptic encephalopathy. However, the molecular action of PIP 2 on K v 7.2 gating remains largely elusive. Here, we use molecular dynamics simulations and electrophysiology to characterize PIP 2 binding sites in a human K v 7.2 channel. In the closed state, PIP 2 localizes to the periphery of the voltage-sensing domain (VSD). In the open state, PIP 2 binds to 4 distinct interfaces formed by the cytoplasmic ends of the VSD, the gate, intracellular helices A and B and their linkers. PIP 2 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 PIP 2 sensitivity of K v 7.2 channels by disrupting PIP 2 binding. These findings reveal the allosteric role of PIP 2 in K v 7.2 channel activation.
Pant et al. (Thu,) studied this question.
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