title: A unique role for the S4 segment of domain 4 in the inactivation of sodium channels.
abstract: Sodium channels have four homologous domains (D1-D4) each with six putative transmembrane segments (S1-S6). The highly charged S4 segments in each domain are postulated voltage sensors for gating. We made 15 charge-neutralizing or -reversing substitutions in the first or third basic residues (arginine or lysine) by replacement with histidine, glutamine, or glutamate in S4 segments of each domain of the human heart Na+ channel. Nine of the mutations cause shifts in the conductance-voltage (G-V) midpoints, and all but two significantly decrease the voltage dependence of peak Na+ current, consistent with a role of S4 segments in activation. The decreases in voltage dependence of activation were equivalent to a decrease in apparent gating charge of 0.5-2.1 elementary charges (eo) per channel for single charge-neutralizing mutations. Three charge-reversing mutations gave decreases of 1.2-1.9 eo per channel in voltage dependence of activation. The steady-state inactivation (h infinity) curves were fit by single-component Boltzmann functions and show significant decreases in slope for 9 of the 15 mutants and shifts of midpoints in 9 mutants. The voltage dependence of inactivation time constants is markedly decreased by mutations only in S4D4, providing further evidence that this segment plays a unique role in activation-inactivation coupling.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia 19104-6059, USA.
authors.forename: L Q
authors.initials: LQ
authors.lastname: Chen
authors.forename: V
authors.initials: V
authors.lastname: Santarelli
authors.forename: R
authors.initials: R
authors.lastname: Horn
authors.forename: R G
authors.initials: RG
authors.lastname: Kallen
mesh_terms: D000818:Animals; D004594:Electrophysiology; D006706:Homeostasis; D006801:Humans; D015640:Ion Channel Gating; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014981:Xenopus
chemical_list: D015222:Sodium Channels