期刊
CIRCULATION RESEARCH
卷 105, 期 4, 页码 383-U151出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.109.197558
关键词
nitric oxide; Kir2.1 channels; resting membrane potential; cardiac myocytes; I-K1
资金
- Ministerio de Educacion y Ciencia [SAF2005-04609, SAF2008-04903]
- Ministerio de Sanidad y Consumo
- Instituto de Salud Carlos III [RD06/0009, PI080665]
- Fundacion LILLY
- Centro Nacional de Investigaciones Cardiovasculares [CNIC-13]
- Comunidad Autonoma de Madrid
Rationale: The cardiac inwardly rectifying K+ current (I-K1) plays a critical role in modulating excitability by setting the resting membrane potential and shaping phase 3 of the cardiac action potential. Objective: This study aims to analyze the effects of nitric oxide (NO) on human atrial I-K1 and on Kir2.1 channels, the major isoform of inwardly rectifying channels present in the human heart. Methods and Results: Currents were recorded in enzymatically isolated myocytes and in transiently transfected CHO cells, respectively. NO at myocardial physiological concentrations (25 to 500 nmol/L) increased inward and outward I-K1 and I-Kir2.1. These effects were accompanied by hyperpolarization of the resting membrane potential and a shortening of the duration of phase 3 of the human atrial action potential. The I-Kir2.1 increase was attributable to an increase in the open probability of the channel. Site-directed mutagenesis analysis demonstrated that NO effects were mediated by the selective S-nitrosylation of Kir2.1 Cys76 residue. Single ion monitoring experiments performed by liquid chromatography/tandem mass spectrometry suggested that the primary sequence that surrounds Cys76 determines its selective S-nitrosylation. Chronic atrial fibrillation, which produces a decrease in NO bioavailability, decreased the S-nitrosylation of Kir2.1 channels in human atrial samples as demonstrated by a biotin-switch assay, followed by Western blot. Conclusions: The results demonstrated that, under physiological conditions, NO regulates human cardiac I-K1 through a redox-related process. (Circ Res. 2009; 105: 383-392.)
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