The extracellular K%2b concentration dependence of outward currents through Kir2.1 channels is regulated by extracellular Na%2b and Ca2%2b
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It has been known for more than three decades that outward Kir currents (IK1) increase with increasing extracellular K%2b concentration ([K%2b]o). Although this increase in I K1 can have significant impacts under pathophysiological cardiac conditions, where [K%2b]o can be as high as 18 mM and thus predispose the heart to re-entrant ventricular arrhythmias, the underlying mechanism has remained unclear. Here, we show that the steep [K %2b]o dependence of Kir2.1-mediated outward IK1 was due to [K%2b]o-dependent inhibition of outward I K1 by extracellular Na%2b and Ca2%2b. This could be accounted for by Na%2b/Ca2%2b inhibition of IK1 through screening of local negative surface charges. Consistent with this, extracellular Na%2b and Ca2%2b reduced the outward single-channel current and did not increase open-state noise or decrease the mean open time. In addition, neutralizing negative surface charges with a carboxylate esterifying agent inhibited outward IK1 in a similar [K%2b]o-dependent manner as Na%2b/Ca2%2b. Site-directed mutagenesis studies identified Asp114 and Glu 153 as the source of surface charges. Reducing K%2b activation and surface electrostatic effects in an R148Y mutant mimicked the action of extracellular Na%2b and Ca2%2b, suggesting that in addition to exerting a surface electrostatic effect, Na%2b and Ca 2%2b might inhibit outward IK1 by inhibiting K%2b activation. This study identified interactions of K%2b with Na %2b and Ca2%2b that are important for the [K%2b] o dependence of Kir2.1-mediated outward IK1. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
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Concentration dependence; Extracellular; Negative surface charges; Pathophysiological; Significant impacts; Single-channel; Site directed mutagenesis; Surface electrostatics; Underlying mechanism; Ventricular arrhythmias; Carboxylation; Charged particles; Electric furnaces; Electrostatics; Enzyme activity; Sodium; Surface charge; Calcium; arginine; aspartic acid; calcium ion; glutamic acid; inwardly rectifying potassium channel subunit Kir2.1; potassium ion; sodium ion; tyrosine; animal tissue; article; controlled study; molecular interaction; mutant; nonhuman; potassium current; priority journal; surface charge; Xenopus; Animals; Calcium; Electric Conductivity; Extracellular Space; Intracellular Space; Models, Molecular; Potassium; Potassium Channels, Inwardly Rectifying; Protein Conformation; Sodium; Static Electricity
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