Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis.
Several heritable forms of myotonia and hyperkalemic periodic paralysis (HyperPP) are caused by missense mutations in the alpha subunit of the skeletal muscle Na channel (SkM1). These mutations impair fast inactivation or shift activation toward hyperpolarized potentials, inducing persistent Na currents that may cause muscle depolarization, myotonia, and onset of weakness. It has been proposed that the aberrant Na current and resulting weakness will be sustained only if Na channel slow inactivation is also impaired. We therefore measured slow inactivation for wild-type and five mutant Na channels constructed in the rat skeletal muscle isoform (rSkM1) and expressed in HEK cells. Two common HyperPP mutations (T698M in domain II-S5 and M1585V in IV-S6) had defective slow inactivation. This defect reduced use-dependent inhibition of Na currents elicited during 50-Hz stimulation. A rare HyperPP mutation (M1353V in IV-S1) and mutations within the domain III-IV linker that cause myotonia (G1299E) or myotonia plus weakness (T1306M) did not impair slow inactivation. We also observed that slow inactivation of wild-type rSkM1 was incomplete; therefore it is possible that stable membrane depolarization and subsequent muscle weakness may be caused solely by defects in fast inactivation or activation. Model simulations showed that abnormal slow inactivation, although not required for expression of a paralytic phenotype, may accentuate muscle membrane depolarization, paralysis, and sensitivity to hyperkalemia.
Hayward
L J
LJ
Department of Neurology, Massachusetts General Hospital, Boston 02114, USA.
Brown
R H
RH
Cannon
S C
SC
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008564:Membrane Potentials; D018482:Muscle, Skeletal / Q000503:physiopathology*; D016254:Mutagenesis, Insertional; D016297:Mutagenesis, Site-Directed; D009222:Myotonia / Q000235:genetics / Q000503:physiopathology*; D010245:Paralyses, Familial Periodic / Q000235:genetics / Q000503:physiopathology*; D017354:Point Mutation; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*; D014162:Transfection
D011994:Recombinant Proteins; D015222:Sodium Channels