The simplest KcsA kinetic cycle contains at least four distinct states, closed and prime-to-conduct (C/O), open and conductive (O/O), open and C-type inactivated (O/I) and closed and C-type inactivated (C/I). KcsA resting state (C/O) is best represented by the structure of its closed state in high-potassium concentration (PDB 1K4C). (a) Upon proton activation, the channel undergoes conformational changes at its activation gate, increasing its diameter to 22 Å, which allows K+ ions to flow down their electrochemical gradient for about 200 ms, just before the onset of C-type inactivation. The Locked-open KcsA E71A mutant (PDB 5VK6) likely represents this short-lived open and conductive state (O/O). (b) A strong allosteric coupling between KcsA’s activation gate and its filter determines the duration of its O/O state. Opening of the channel activation gate is communicated to the filter by mechanical deformation that propagates along a network of interacting amino-acid residues along the second membrane-spanning segment. Among many, Phe 103 undergoes conformational changes (yellow spheres) that make it clash with Thr 75 on the channel’s pore helix, triggering a series of structural rearrangement at the channel’s filter that yield a pore with two consecutive ion vacancies and collapsed or deep C-type inactivated. The Locked-open KcsA Y82A mutant structure (PDB 5VKE) recapitulates the most important features of KcsA’s O/I state. (c) Decreasing intracellular proton concentration triggers KcsA deactivation gating, which involves structural rearrangements that close the channel’s activation gate. For a brief period of time, KcsA exists with a collapsed filter and its activation gate closed. The structural model that best describes KcsA’s C/I state is the closed structure in low K+ concentration (PDB 1K4D). (d) Once the KcsA activation gate is closed, the filter remains collapsed for an undetermined period of time, though computational calculations have suggested that the exit of the ‘inactivating waters’ from the ‘inactivation cavity’ determines the recovery rate of the channel’s filter.