Nitric oxide increases cardiac IK1 by nitrosylation of cysteine 76 of Kir2.1 channels.

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 Res

journal_title

Circulation research

authors

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 E

doi

10.1161/CIRCRESAHA.109.197558

subject

Has Abstract

pub_date

2009-08-14 00:00:00

pages

383-92

issue

4

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.109.197558

journal_volume

105

pub_type

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