title: Two mutations in the IV/S4-S5 segment of the human skeletal muscle Na+ channel disrupt fast and enhance slow inactivation.
abstract: 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.
authors.affiliation: Department of Applied Physiology, University of Ulm, Helmholtzstr. 8/1, D-89069 Ulm, Germany.
authors.forename: A K
authors.initials: AK
authors.lastname: Alekov
authors.forename: W
authors.initials: W
authors.lastname: Peter
authors.forename: N
authors.initials: N
authors.lastname: Mitrovic
authors.forename: F
authors.initials: F
authors.lastname: Lehmann-Horn
authors.forename: H
authors.initials: H
authors.lastname: Lerche
mesh_terms: 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*
chemical_list: D015222:Sodium Channels