title: Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states.
abstract: The TREK subfamily of two-pore domain (K2P) K(+) channels exhibit polymodal gating by a wide range of physical and chemical stimuli. Crystal structures now exist for these channels in two main states referred to as the "up" and "down" conformations. However, recent studies have resulted in contradictory and mutually exclusive conclusions about the functional (i.e., conductive) status of these two conformations. To address this problem, we have used the state-dependent TREK-2 inhibitor norfluoxetine that can only bind to the down state, thereby allowing us to distinguish between these two conformations when activated by different stimuli. Our results reconcile these previously contradictory gating models by demonstrating that activation by pressure, temperature, voltage, and pH produce more than one structurally distinct open state and reveal that channel activation does not simply involve switching between the up and down conformations. These results also highlight the diversity of structural mechanisms that K2P channels use to integrate polymodal gating signals.
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, England, UK OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PU, England, UK.
authors.forename: Conor
authors.initials: C
authors.lastname: McClenaghan
authors.affiliation: Department of Physiology, University of Kiel, 24118 Kiel, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schewe
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, England, UK OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PU, England, UK.
authors.forename: Prafulla
authors.initials: P
authors.lastname: Aryal
authors.affiliation: OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PU, England, UK Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, England, UK.
authors.forename: Elisabeth P
authors.initials: EP
authors.lastname: Carpenter
authors.affiliation: Department of Physiology, University of Kiel, 24118 Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Baukrowitz
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, England, UK OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PU, England, UK stephen.tucker@physics.ox.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
mesh_terms: D000818:Animals; D006801:Humans; D015640:Ion Channel Gating; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry / Q000378:metabolism*; D014981:Xenopus
chemical_list: C503438:KCNK10 protein, human; D024683:Potassium Channels, Tandem Pore Domain