Molecular Basis for Activation to Inhibition Switching in Kv7.2 Channel Modulators

Kv7 voltage‐gated potassium channels play a critical role in controlling electrical properties of excitable tissues. Neuronally‐expressed Kv7 channels are involved in both common and rare neuropsychiatric disorders, ranging from epilepsy to depression and neurodegenerative diseases; thus, they represent attractive therapeutic targets. However, no Kv7 modulator is currently available for clinical use. Improved knowledge of the functional and structural determinants responsible for ligand‐induced Kv7 channel modulation is likely to fill this gap. In the present work, we describe the cryo‐electron microscopy structures of human Kv7.2 channels in complex with two retigabine analogues: compound 60 ( c60 ), which we previously described as a Kv7 activator with improved pharmacokinetic and pharmacodynamic properties, and the newly designed compound 106 ( c106 ), which acts as a potent Kv7 blocker. Although both compounds occupy the same pocket at the S5–S6 interface in the pore domain, docking and molecular dynamics simulations and electrophysiological experiments revealed that the opposite functional behavior is due to their differential interaction, involving the L307 residue. Thus, we herein provide novel mechanistic insights into the molecular mechanisms governing Kv7 channel modulation by exogenous ligands which may prove useful to target Kv7 channels with more potent and selective modulators.