SignificanceVoltage-gated ion channels underlie electrical signaling in cells. The structures and functions of voltage-dependent K+, Na+, and Ca2+and transient receptor potential ion channels have been studied extensively since their discovery. Despite these efforts, it is still not well understood how the voltage sensors in these different ion channels change their conformation in response to membrane voltage changes, and how these movements regulate the opening or closing of the channel’s gate. This study presents structures of the human KCNQ1 (Kv7.1) voltage–dependent and phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent K+channel in electrically polarized lipid vesicles using cryogenic electron microscopy, showing how the voltage sensors influence gating indirectly by regulating the ability of PIP2to bind to the channel.