Two mutations in the IV/S4-S5 segment of the human skeletal muscle Na+ channel disrupt fast and enhance slow inactivation.
Fast and slow inactivation (FI, SI) of the voltage-gated Na+ channel are two kinetically distinct and structurally dissociated processes. The voltage sensor IV/S4 and the intracellular IV/S4-S5 loop have been shown to play an important role in FI mediating the coupling between activation and inactivation. Two mutations in IV/S4-S5 of the human muscle Na+ channel, L1482C/A, disrupt FI by inducing a persistent Na+ current, shifting steady-state inactivation in the depolarizing direction and accelerating its recovery. These effects were more pronounced for L1482A. In contrast, SI of L1482C/A channels was enhanced showing a more complete SI and a 3-fold slowing of its recovery. Effects on SI were more pronounced for L1482C. The results indicate an important role of the IV/S4-S5 loop not only in FI but also in SI of the Na+ channel.
Alekov
A K
AK
Department of Applied Physiology, University of Ulm, Helmholtzstr. 8/1, D-89069 Ulm, Germany.
Peter
W
W
Mitrovic
N
N
Lehmann-Horn
F
F
Lerche
H
H
D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D008564:Membrane Potentials / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed / Q000502:physiology; D009222:Myotonia / Q000235:genetics / Q000378:metabolism; D010243:Paralysis / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*
D015222:Sodium Channels