Ca2+-calmodulin regulates Kv7.1 channel gating by allosterically interfering with its inactivation path

Like in many voltage-gated K+ channels (Kv), inactivation of the cardiac Kv7.1 channel is voltage-dependent but does not exhibit the hallmarks of N-type or C-type mechanisms. This peculiar inactivation is observed in wild-type channels and is exacerbated in many Kv7.1 mutations triggering cardiac arrhythmias. Previously, we showed that Kv7.1 inactivation could strikingly be prevented by Ca2+-calmodulin (Ca2+-CaM). Thus, how can Ca2+-CaM, localized at the channel inner boundaries, prevent inactivation that occurs distantly at the outer pore region and converges to the selectivity filter? Here, using network analysis, molecular dynamics simulations, and electrophysiology, we identify the inactivation paths coupling the voltage sensor domain to the selectivity filter, involving helices S1 and S6, and the P-Helix, which represents the underlying mechanism of Kv7.1 inactivation. Moreover, our data reveal the allosteric coupling mechanisms by which Ca2+-CaM signals interfere with the inactivation paths and prevent channel inactivation.