title: Synergistic interplay of Gβγ and phosphatidylinositol 4,5-bisphosphate dictates Kv7.4 channel activity.
abstract: Kv7.4 channels are key determinants of arterial contractility and cochlear mechanosensation that, like all Kv7 channels, have an obligatory requirement for phosphatidylinositol 4,5-bisphosphate (PIP2). βγ G proteins (Gβγ) have been identified as novel positive regulators of Kv7.4. The present study ascertained whether Gβγ increased Kv7.4 open probability through an increased sensitivity to PIP2. In HEK cells stably expressing Kv7.4, PIP2or Gβγ increased open probability in a concentration dependent manner. Depleting PIP2prevented any Gβγ-mediated stimulation whilst an array of Gβγ inhibitors prohibited any PIP2-induced current enhancement. A combination of PIP2and Gβγ at sub-efficacious concentrations increased channel open probability considerably. The stimulatory effects of three Kv7.2-7.5 channel activators were also lost by PIP2depletion or Gβγ inhibitors. This study alters substantially our understanding of the fundamental processes that dictate Kv7.4 activity, revealing a more complex and subtle paradigm where the reliance on local phosphoinositide is dictated by interaction with Gβγ.
authors.affiliation: Vascular Biology Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, London, SW17 0RE, UK.
authors.forename: Oleksandr V
authors.initials: OV
authors.lastname: Povstyan
authors.affiliation: Vascular Biology Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, London, SW17 0RE, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Barrese
authors.affiliation: Vascular Biology Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, London, SW17 0RE, UK.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Stott
authors.affiliation: Vascular Biology Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, London, SW17 0RE, UK. grenwood@sgul.ac.uk.
authors.forename: Iain A
authors.initials: IA
authors.lastname: Greenwood
mesh_terms: D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism
chemical_list: D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D019204:GTP-Binding Proteins
keywords: G-protein βγ; Ion channel regulation; KCNQ; PIP2; Potassium channel