SODIUM-CHANNEL MUTATIONS IN PARAMYOTONIA-CONGENITA EXHIBIT SIMILAR BIOPHYSICAL PHENOTYPES IN-VITRO

Mutations in the skeletal muscle voltage-gated Na+ channel cu-subunit have been found in patients with two distinct hereditary disorders of sarcolemmal excitation: hyperkalemic periodic paralysis (HYPP) and par amyotonia congenita (PC). Six of these mutations have been functionall y expressed in a heterologous cell line (tsA201 cells) using the recom binant human skeletal muscle Na+ channel alpha-subunit cDNA hSkM1. PC mutants from diverse locations in this subunit (T1313M, L1433R, R1448H , R1448C, A1156T) ail exhibit a similar disturbance in channel inactiv ation characterized by reduced macroscopic rate, accelerated recovery, and altered voltage dependence. PC mutants had no significant abnorma lity in activation. In contrast, one HYPP mutation studied (T704M) has a normal inactivation rate but exhibits shifts in the midpoints of st eady-state activation and inactivation along the voltage axis. These f indings help to explain the phenotypic differences between HYPP and PC at the molecular and biophysical level and contribute to our understa nding of Na+ channel structure and function.