title: The cytosolic GH loop regulates the phosphatidylinositol 4,5-bisphosphate-induced gating kinetics of Kir2 channels.
abstract: Inwardly rectifying K(+) (Kir) channels set the resting membrane potential and regulate cellular excitability. The activity of Kir channels depends critically on the phospholipid PIP(2). The molecular mechanism by which PIP(2) regulates Kir channel gating is poorly understood. Here, we utilized a combination of computational and electrophysiological approaches to discern structural elements involved in regulating the PIP(2)-induced gating kinetics of Kir2 channels. We identify a novel role for the cytosolic GH loop. Mutations that directly or indirectly affect GH loop flexibility (e.g. V223L, E272G, D292G) increase both the on- and especially the off-gating kinetics. These effects are consistent with a model in which competing interactions between the CD and GH loops for the N terminus regulate the gating of the intracellular G loop gate.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Hai-Long
authors.initials: HL
authors.lastname: An
authors.forename: Shou-Qin
authors.initials: SQ
authors.lastname: Lü
authors.forename: Jun-Wei
authors.initials: JW
authors.lastname: Li
authors.forename: Xuan-Yu
authors.initials: XY
authors.lastname: Meng
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhan
authors.forename: Meng
authors.initials: M
authors.lastname: Cui
authors.forename: Mian
authors.initials: M
authors.lastname: Long
authors.forename: Hai-Lin
authors.initials: HL
authors.lastname: Zhang
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
mesh_terms: D000818:Animals; D015640:Ion Channel Gating / Q000502:physiology*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D024661:Potassium Channels, Inwardly Rectifying