title: Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores.
abstract: Voltage-gated ion channels sense voltage by shuttling arginine residues located in the S4 segment across the membrane electric field. The molecular pathway for this arginine permeation is not understood, nor is the filtering mechanism that permits passage of charged arginines but excludes solution ions. We find that substituting the first S4 arginine with smaller amino acids opens a high-conductance pathway for solution cations in the Shaker K(+) channel at rest. The cationic current does not flow through the central K(+) pore and is influenced by mutation of a conserved residue in S2, suggesting that it flows through a protein pathway within the voltage-sensing domain. The current can be carried by guanidinium ions, suggesting that this is the pathway for transmembrane arginine permeation. We propose that when S4 moves it ratchets between conformations in which one arginine after another occupies and occludes to ions the narrowest part of this pathway.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Tombola
authors.forename: Medha M
authors.initials: MM
authors.lastname: Pathak
authors.forename: Ehud Y
authors.initials: EY
authors.lastname: Isacoff
mesh_terms: D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D001120:Arginine / Q000737:chemistry*; D002412:Cations / Q000737:chemistry*; D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D005260:Female; D019791:Guanidine / Q000494:pharmacology; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000235:genetics; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009865:Oocytes / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D051637:Shaker Superfamily of Potassium Channels; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D002412:Cations; D015221:Potassium Channels; D051637:Shaker Superfamily of Potassium Channels; D001120:Arginine; D019791:Guanidine