title: A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K(+) Channels.
abstract: Two-pore domain (K2P) K(+) channels are major regulators of excitability that endow cells with an outwardly rectifying background "leak" conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of three to four ions into the high electric field of an inactive selectivity filter. Overall, this ion-flux gating mechanism generates a one-way "check valve" within the filter because outward movement of K(+) induces filter opening, whereas inward movement promotes inactivation. Furthermore, many physiological stimuli switch off this flux gating mode to convert K2P channels into a leak conductance. These findings provide insight into the functional plasticity of a K(+)-selective filter and also refine our understanding of K2P channels and the mechanisms by which ion channels can sense voltage.
authors.affiliation: Institute of Physiology, Christian-Albrechts University, 24118 Kiel, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schewe
authors.affiliation: Institute of Physiology, Christian-Albrechts University, 24118 Kiel, Germany.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Nematian-Ardestani
authors.affiliation: Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
authors.forename: Han
authors.initials: H
authors.lastname: Sun
authors.affiliation: Institute of Physiology, Christian-Albrechts University, 24118 Kiel, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Musinszki
authors.affiliation: Institute of Physiology, Christian-Albrechts University, 24118 Kiel, Germany.
authors.forename: Sönke
authors.initials: S
authors.lastname: Cordeiro
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bucci
authors.affiliation: Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Bert L
authors.initials: BL
authors.lastname: de Groot
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; OXION Initiative, University of Oxford, Oxford OX1 3PU, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
authors.affiliation: Institute of Physiology, Christian-Albrechts University, 24118 Kiel, Germany; Nanion Technologies GmbH, 80636 Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Rapedius
authors.affiliation: Institute of Physiology, Christian-Albrechts University, 24118 Kiel, Germany. Electronic address: t.baukrowitz@physiologie.uni-kiel.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Baukrowitz
mesh_terms: D004594:Electrophysiology; D006801:Humans; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011188:Potassium / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*
chemical_list: D024683:Potassium Channels, Tandem Pore Domain; D011188:Potassium