Inverse Modes of Coupling in Leak and Voltage-activated K+ Channel Pore Gates Underlie their Distinct Roles in Electrical Signaling

Voltage-activated (Kv) and leak (K2P) potassium channels play key, yet distinct roles in electrical signaling in the nervous system. Here, we examined how differences in the operation of the activation and slow inactivation pore gates of Kv and K2P channels underlie their unique roles in electrical signaling. We report that (1) leak potassium channels possess a lower activation gate, (2) the activation gate is an important determinant controlling the conformational stability of the K+ channel pore, (3) the lower activation and upper slow inactivation gates of leak channels cross-talk and (4) in contrast to Kv channels, where the two pore gates are negatively-coupled these two gates are positively-coupled in K2P channels. Our results thus demonstrate how basic thermodynamic properties of the K+ channel pore, particularly conformational stability and coupling between the pore gates, underlie the specialized roles of Kv and K2P channel families in electrical signaling.