title: TWIK-1 two-pore domain potassium channels change ion selectivity and conduct inward leak sodium currents in hypokalemia.
abstract: Background potassium (K+) channels, which are normally selectively permeable to K+, maintain the cardiac resting membrane potential at around -80 mV. In subphysiological extracellular K+ concentrations ([K+]o), which occur in pathological hypokalemia, the resting membrane potential of human cardiomyocytes can depolarize to around -50 mV, whereas rat and mouse cardiomyocytes become hyperpolarized, consistent with the Nernst equation for K+. This paradoxical depolarization of cardiomyocytes in subphysiological [K+]o, which may contribute to cardiac arrhythmias, is thought to involve an inward leak sodium (Na+) current. Here, we show that human cardiac TWIK-1 (also known as K2P1) two-pore domain K+ channels change ion selectivity, becoming permeable to external Na+, and conduct inward leak Na+ currents in subphysiological [K+]o. A specific threonine residue (Thr118) within the pore selectivity sequence TxGYG was required for this altered ion selectivity. Mouse cardiomyocyte-derived HL-1 cells exhibited paradoxical depolarization with ectopic expression of TWIK-1 channels, whereas TWIK-1 knockdown in human spherical primary cardiac myocytes eliminated paradoxical depolarization. These findings indicate that ion selectivity of TWIK-1 K+ channels changes during pathological hypokalemia, elucidate a molecular basis for inward leak Na+ currents that could trigger or contribute to cardiac paradoxical depolarization in lowered [K+]o, and identify a mechanism for regulating cardiac excitability.
authors.affiliation: Department of Biological Sciences, University at Albany, State University of New York, Albany, NY 12222, USA.
authors.forename: Liqun
authors.initials: L
authors.lastname: Ma
authors.forename: Xuexin
authors.initials: X
authors.lastname: Zhang
authors.forename: Haijun
authors.initials: H
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002463:Cell Membrane Permeability; D006801:Humans; D007008:Hypokalemia / Q000209:etiology / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D012964:Sodium / Q000378:metabolism*
chemical_list: C109137:KCNK1 protein, human; C486372:Kcnk1 protein, mouse; D024683:Potassium Channels, Tandem Pore Domain; D012964:Sodium; D011188:Potassium