title: Differential roles of S6 domain hinges in the gating of KCNQ potassium channels.
abstract: Voltage-gated K+ channel activation is proposed to result from simultaneous bending of all S6 segments away from the central axis, enlarging the aperture of the pore sufficiently to permit diffusion of K+ into the water-filled central cavity. The hinge position for the bending motion of each S6 segment is proposed to be a Gly residue and/or a Pro-Val-Pro motif in Kv1-Kv4 channels. The KCNQ1 (Kv7.1) channel has Ala-336 in the Gly-hinge position and Pro-Ala-Gly. Here we show that mutation of Ala-336 to Gly in KCNQ1 increased current amplitude and shifted the voltage dependence of activation to more negative potentials, consistent with facilitation of hinge activity that favors the open state. In contrast, mutation of Ala-336 to Cys or Thr shifted the voltage dependence of activation to more positive potentials and reduced current amplitude. Mutation of the putative Gly hinge to Ala in KCNQ2 (Kv7.2) abolished channel function. Mutation-dependent changes in current amplitude, but not kinetics, were found in heteromeric KCNQ1/KCNE1 channels. Mutation of the Pro or Gly of the Pro-Ala-Gly motif to Ala abolished KCNQ1 function and introduction of Gly in front of the Ala-mutations partially recovered channel function, suggesting that flexibility at the PAG is important for channel activation.
authors.affiliation: Physiologisches Institut I, Universität Tübingen, D-72076 Tübingen, Germany. guiscard.seebohm@gmx.de
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strutz-Seebohm
authors.forename: Oana N
authors.initials: ON
authors.lastname: Ureche
authors.forename: Ravshan
authors.initials: R
authors.lastname: Baltaev
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
authors.forename: Ganna
authors.initials: G
authors.lastname: Kornichuk
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Kamiya
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Wuttke
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D015640:Ion Channel Gating / Q000502:physiology*; D051657:KCNQ1 Potassium Channel / Q000737:chemistry* / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000502:physiology*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D051657:KCNQ1 Potassium Channel