Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis

A novel mutation in a family with hypokalemic periodic paralysis is describ ed. The mutation R672S is located in the voltage sensor segment S4 of domai n II in the SCN4A gene encoding the human skeletal muscle voltage-gated sod ium channel. Functional expression of the R672S channels in human embryonic kidney 293 cells revealed a small but significant hyperpolarizing shift in the steady-state fast inactivation, and a dramatic enhancement in channel slow inactivation. These two defects are mainly due to a slow recovery of t he mutant channels from fast and/or slow inactivation. Our data may help ex plain the mechanism underlying hypokalemic periodic paralysis and the patie nt's worsening from acetazolamide.