Electric field-induced pore constriction in the human Kv2.1 channel

Gating in voltage-dependent ion channels is regulated by the transmembrane voltage. This form of regulation is enabled by voltage sensing domains (VSDs) that respond to transmembrane voltage differences by changing their conformation and exerting force on the pore to open or close it. Here we use cryogenic electron microscopy to study the neuronal Kv2.1 channel in lipid vesicles with and without a voltage difference across the membrane. Hyperpolarizing voltage differences displace the positively charged S4 helix in the voltage sensor by one helical turn ([~]5 [A]). When this displacement occurs, the S4 helix changes its contact with the pore at two different interfaces. When these changes are observed in fewer than four voltage sensors the pore remains open, but when they are observed in all four voltage sensors the pore constricts. The constriction occurs because the S4 helix, as it displaces inward, squeezes the right-handed helical bundle of pore lining S6 helices. A similar conformational change occurs upon hyperpolarization of the EAG1 channel. Therefore, while Kv2.1 and EAG1 are from distinct architectural classes of voltage-dependent ion channels, called domain-swapped and nondomain-swapped, the manner in which the voltage sensors gate their pores is very similar. Significance StatementOur ability to transmit signals across long distances rapidly - for example an instruction from the brain to the muscles in our fingers - depends on electrical impulses that travel along nerve cells. These electrical signals are mediated by membrane proteins called voltage-dependent ion channels. These channels have voltage sensors, which are domains that sense the voltage difference across the cell membrane and switch the channel on or off accordingly. Scientists discovered two architectural classes of voltage-dependent ion channels distinguished by the different ways the voltage sensors attach to the pore. This study shows that the two architectures are not very different after all because they both solve the problem of regulation of the pore by voltage sensors in the same way.