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Sci. Signal., 7 June 2011
Vol. 4, Issue 176, p. ra37
[DOI: 10.1126/scisignal.2001726]

RESEARCH ARTICLES

TWIK-1 Two-Pore Domain Potassium Channels Change Ion Selectivity and Conduct Inward Leak Sodium Currents in Hypokalemia

Liqun Ma, Xuexin Zhang, and Haijun Chen*

Department of Biological Sciences, University at Albany, State University of New York, Albany, NY 12222, USA.

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.

* To whom correspondence should be addressed. E-mail: hchen01{at}albany.edu

Citation: L. Ma, X. Zhang, H. Chen, TWIK-1 Two-Pore Domain Potassium Channels Change Ion Selectivity and Conduct Inward Leak Sodium Currents in Hypokalemia. Sci. Signal. 4, ra37 (2011).

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