| Voltage-gated sodium channels initiate and propagate electrical signaling in excitable tissues by conducting sodium ions through a central pore module, formedby four domains (DI-DIV)that alsocontainhomologous voltage sensormodules. Changes in membrane potential drive conformational changes of the voltage sensors(promoting activation, inactivation,ordeactivation), thatopen or closethe central pore. Voltage sensormodule mutationsdisrupt channel gating, causing diseases of electrical excitability such as hypokalemic periodic paralysis. This diseaseischaracterized by skeletal muscle weakness associated with low serum potassium andis caused by mutations in the voltage-sensitive S4 segments within the DI-DIIIvoltage sensormodules. Here, Iuse electrophysiological and multi-scale modelling approachesto isolate gating defects caused by three homologous hypokalemic periodic paralysis mutations, identify novel rolesforgating defects in the pathology of this disease, and define electrostatic interactions and critical residues within the DIand DIV voltage sensors that drive activation.Keywords: sodium channels, molecular dynamics, cut-open voltage clamp electrophysiology, free energy, action potentials |