Abstract:
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.
journal_name
Circ Resjournal_title
Circulation researchauthors
Gómez R,Caballero R,Barana A,Amorós I,Calvo E,López JA,Klein H,Vaquero M,Osuna L,Atienza F,Almendral J,Pinto A,Tamargo J,Delpón Edoi
10.1161/CIRCRESAHA.109.197558subject
Has Abstractpub_date
2009-08-14 00:00:00pages
383-92issue
4eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.109.197558journal_volume
105pub_type
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