KCNKO: Opening and closing the 2-P-domain potassium leak channel entails C-type gating of the outer pore

Essential to nerve and muscle function, little is known about how potassium leak channels operate. KCNKO opens and closes in a kinase-dependent fashion. Here, the transition is shown to correspond to changes in the outer aspect of the ion conduction pore. Voltage-gated potassium (VGK) channels open and close via an internal gate; however, they also have an outer pore gate that produces C-type inactivation. While KCNKO does not inactivate, KCNKO and VGK channels respond in like manner to outer pore blockers, potassium, mutations, and chemical modifiers. Structural relatedness is confirmed: VGK residues that come close during C-type gating predict KCNKO sites that crosslink (after mutation to cysteine) to yield channels controlled by reduction and oxidization. We conclude that similar outer pore gates mediate KCNKO opening and closing and VGK channel C-type inactivation despite their divergent structures and physiological roles.