title: Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: involvement of the S4/S5 linker and the S6 segment.
abstract: GoSlo-SR-5-6 is a novel large-conductance Ca(2+)-activated K(+) (BK) channel agonist that shifts the activation V1/2 of these channels in excess of -100 mV when applied at a concentration of 10 μM. Although the structure-activity relationship of this family of molecules has been established, little is known about how they open BK channels. To help address this, we used a combination of electrophysiology, mutagenesis, and mathematical modeling to investigate the molecular mechanisms underlying the effect of GoSlo-SR-5-6. Our data demonstrate that the effects of this agonist are practically abolished when three point mutations are made: L227A in the S4/S5 linker in combination with S317R and I326A in the S6C region. Our data suggest that GoSlo-SR-5-6 interacts with the transmembrane domain of the channel to enhance pore opening. The Horrigan-Aldrich model suggests that GoSlo-SR-5-6 works by stabilizing the open conformation of the channel and the activated state of the voltage sensors, yet decouples the voltage sensors from the pore gate.
authors: Ion Channel Biotechnology Centre and.
authors: Timothy I
authors: TI
authors: Webb
authors: The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, County Louth, Ireland.
authors: Aravind Singh
authors: AS
authors: Kshatri
authors: Ion Channel Biotechnology Centre and.
authors: Roddy J
authors: RJ
authors: Large
authors: The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, County Louth, Ireland.
authors: Adebola Morayo
authors: AM
authors: Akande
authors: Ion Channel Biotechnology Centre and.
authors: Subhrangsu
authors: S
authors: Roy
authors: Ion Channel Biotechnology Centre and The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, County Louth, Ireland.
authors: Gerard P
authors: GP
authors: Sergeant
authors: Ion Channel Biotechnology Centre and The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, County Louth, Ireland.
authors: Noel G
authors: NG
authors: McHale
authors: Ion Channel Biotechnology Centre and The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, County Louth, Ireland.
authors: Keith D
authors: KD
authors: Thornbury
authors: Ion Channel Biotechnology Centre and The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, County Louth, Ireland mark.hollywood@dkit.ie.
authors: Mark A
authors: MA
authors: Hollywood
mesh_terms: D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D016296:Mutagenesis
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels
keywords: ion channels; modulators; structure function
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