An important piece has been placed in the puzzle of hypokalemic periodic paralysis

Hypokalemic periodic paralysis (HypoPP) is a fascinating disorder of muscle membrane excitability because at first glance it does not make sense. Why should a muscle fiber depolarize when the extracellular potassium concentration is reduced? Everyone knows that elevated potassium concentration depolarizes cells and that reduced extracellular potassium should hyperpolarize a cell! The apparently paradoxical response of skeletal muscle from patients with HypoPP has been a mystery of membrane physiology. Another feature of HypoPP that is somewhat counterintuitive is that the same (or similar) phenotype can result from mutations of 2 different ion channels, the l-type skeletal muscle calcium channel, CaV1.1, or the skeletal muscle voltage-gated sodium channel, NaV1.4. The article by Francis et al.1 contributes an important piece to resolving the puzzle of HypoPP by establishing a common mechanism causing the depolarization in HypoPP—though not the paramyotonia—for all the known NaV1.4 channel mutations associated with HypoPP. Earlier studies of the muscle membrane from patients with HypoPP showed that the paradoxical response in the presence of reduced extracellular potassium concentration was due to a depolarizing current. This pathologic current was not blocked by tetrodotoxin,2,3 which blocks the ion pore of voltage-gated sodium channels, or by nitrendipine,3 which blocks l-type calcium channels. Tetrodotoxin and nitrendipine blocked sodium and calcium currents in HypoPP muscle.3 The pathologic current thus did not travel through the normal conductance pores of NaV1.4 or …