The voltage-gated potassium channel KCNQ2 is responsible for M-current in neurons and is an important drug target to treat epilepsy,pain and several other diseases related to neuronal hyper-excitability.A list of synthetic compounds have been developed to directly activate KCNQ2,yet our knowledge of their activation mechanism is limited,due to lack of high-resolution structures.Here,we report cryo-electron microscopy(cryo-EM)structures of the human KCNQ2 determined in apo state and in complex with two activators,ztz240 or retigabine,which activate KCNQ2 through different mechanisms.The activator-bound structures,along with electrophysiology analysis,reveal that ztz240 binds at the voltage-sensing domain and directly stabilizes it at the activated state,whereas retigabine binds at the pore domain and activates the channel by an allosteric modulation.By accurately defining ligand-binding sites,these KCNQ2 structures not only reveal different ligand recognition and activation mechanisms,but also provide a structural basis for drug optimization and design.