title: Physical determinants of strong voltage sensitivity of K(+) channel block.
abstract: Strong voltage sensitivity of inward-rectifier K(+) (Kir) channels has been hypothesized to arise primarily from an intracellular blocker displacing up to five K(+) ions from the wide, intracellular part of the ion conduction pore outwardly across the narrow ion-selectivity filter. The validity of this hypothesis depends on two assumptions: (i) that five ion sites are located intracellular to the filter and (ii) that the blocker can force essentially unidirectional K(+) movement in a pore region generally wider than the combined dimensions of the blocker plus a K(+) ion. Here we present a crystal structure of the cytoplasmic portion of a Kir channel with five ions bound and demonstrate that a constriction near the intracellular end of the pore, acting as a gasket, prevents K(+) ions from bypassing the blocker. This heretofore unrecognized 'gasket' ensures that the blocker can effectively displace K(+) ions across the selectivity filter to generate exceedingly strong voltage sensitivity.
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.forename: Hyeon-Gyu
authors.initials: HG
authors.lastname: Shin
authors.forename: Szilvia
authors.initials: S
authors.lastname: Szép
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000818:Animals; D002412:Cations / Q000378:metabolism*; D018360:Crystallography, X-Ray; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D002412:Cations; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D026902:Potassium Channel Blockers; D011188:Potassium