Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism

Núñez, Lucı́a; Vaquero, Luis M.; Gómez, Ricardo; Caballero, Ricardo; Mateos-Cáceres, Petra J.; Macaya, Carlos; Iriepa, Isabel; Galvez, Enrique J.; López‐Farré, Antonio; Tamargo, Juan; Delpón, Eva

doi:10.1016/j.cardiores.2006.06.021

Cited by 75 publications

(61 citation statements)

References 46 publications

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“…Accordingly, bond dissociation energies of RSNO are reported to vary from Ϸ22 to 32 kcal⅐mol Ϫ1 (6, 26), and the dissociation constants of FeNO can vary by a factor of Ͼ10 6 (13, 23, 24), translating to intrinsic FeNO/SNO lifetimes ranging from seconds to years. Environmental factors that have been reported to influence SNO stability and reactivity, directly or through elicited conformational changes in proteins, include pH (low and high) (5,6,20,26), metal ions (Ca, Mg, Cu, and Fe) (6,14,20,27,28), nucleophiles (ascorbate, thiolate, and amine) (6, 13), local hydrophobicity (denaturants) (29), oxidants and reductants (6, 19), proteolytic enzymes (30), alkylators (31), O 2 tension (5, 32), and various intramolecular interactions (H-bonding, S-, N-, O-coordination, and aromatic residue interactions) (6,16,20,22,(33)(34)(35)(36). Many of these factors also affect FeNO stability (17,23,24).…”

Section: Red Blood Cell Vasodilation ͉ S-nitrosohemoglobin ͉ S-nitrosmentioning

confidence: 99%

Assessment of nitric oxide signals by triiodide chemiluminescence

Hausladen

Rafikov

Angelo

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

101

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Nitric oxide (NO) bioactivity is mainly conveyed through reactions with iron and thiols, furnishing iron nitrosyls and S-nitrosothiols with wide-ranging stabilities and reactivities. Triiodide chemiluminescence methodology has been popularized as uniquely capable of quantifying these species together with NO byproducts, such as nitrite and nitrosamines. Studies with triiodide, however, have challenged basic ideas of NO biochemistry. The assay, which involves addition of multiple reagents whose chemistry is not fully understood, thus requires extensive validation: Few protein standards have in fact been characterized; NO mass balance in biological mixtures has not been verified; and recovery of species that span the range of NO-group reactivities has not been assessed. Here we report on the performance of the triiodide assay vs. photolysis chemiluminescence in side-by-side assays of multiple nitrosylated standards of varied reactivities and in assays of endogenous Fe-and S-nitrosylated hemoglobin. Although the photolysis method consistently gives quantitative recoveries, the yields by triiodide are variable and generally low (approaching zero with some standards and endogenous samples). Moreover, in triiodide, added chemical reagents, changes in sample pH, and altered ionic composition result in decreased recoveries and misidentification of NO species. We further show that triiodide, rather than directly and exclusively producing NO, also produces the highly potent nitrosating agent, nitrosyliodide. Overall, we find that the triiodide assay is strongly influenced by sample composition and reactivity and does not reliably identify, quantify, or differentiate NO species in complex biological mixtures. red blood cell vasodilation ͉ S-nitrosohemoglobin ͉ S-nitrosylationT he biological effects of nitric oxide (NO) are mediated in large part through binding to transition metals and cysteine thiols at active or allosteric sites within regulatory proteins (1), which elicits changes in protein activity, protein-protein interactions, and protein location (1). Within tissues, many dozens of S-nitrosylated proteins have been identified, and signatures of NO bound to nonheme and heme iron have been detected (1, 2). Additionally, NO can be transported in endocrine or paracrine fashion by reacting with heme iron and cysteine thiols in proteins [hemoglobin (Hb) and albumin] and peptides (glutathione and cysteinlyglycine) to form NO adducts with longer biological lifetimes (3-5); release of NO bioactivity from stable adducts is effected by allosteric and redox-based mechanisms that alter FeNO or S-nitrosothiol (SNO) reactivity (5, 6). An updated discussion of the factors influencing reactivity of S-nitrosohemoglobin, S-nitrosoalbumin, and low-molecular-weight SNO in the context of vasoregulation (5-15) can be found in supporting information (SI) Text.The dynamic distribution of protein and low-molecular-weight NO compounds that subserve NO transport and signaling instantiate the variation in both FeNO and SNO reactivities (4,6,13...

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Section: Red Blood Cell Vasodilation ͉ S-nitrosohemoglobin ͉ S-nitrosmentioning

confidence: 99%

Assessment of nitric oxide signals by triiodide chemiluminescence

Hausladen

Rafikov

Angelo

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

101

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“…4 The role of I Kur in atrial repolarization depends strongly on action potential morphology and is increased with the short-duration, triangular action potentials that occur in AF. 52 Oxidant production is increased in ATR and AF, 53,54 and Kv1.5 currents are inhibited by oxidation by S-nitrosylation, 55 which may contribute to I Kur suppression in AF. The delayed-rectifier currents I Kr and I Ks are not changed in experimental ATR, 5 and information from AF patients is lacking, likely because of difficulties in recording I Kr and I Ks in human atrial cardiomyocytes isolated by the "chunk" method.…”

Section: Voltage-gated Kmentioning

confidence: 99%

Atrial Remodeling and Atrial Fibrillation

Nattel

Burstein

Dobrev

2008

Circ: Arrhythmia and Electrophysiology

905

644

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A trial fibrillation (AF) is the most common arrhythmia in clinical practice. It can occur at any age but is very rare in children and becomes extremely common in the elderly, with a prevalence approaching 20% in patients Ͼ85 years of age. 1 AF is associated with a wide range of potential complications and contributes significantly to population morbidity and mortality. Present therapeutic approaches to AF have major limitations, including limited efficacy and significant adverse effect liability. These limitations have inspired substantial efforts to improve our understanding of the mechanisms underlying AF, with the premise that improved mechanistic insights will lead to innovative and improved therapeutic approaches. 2

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“…Furthermore, a direct reaction between NO and thiol groups on cysteine residues causes changes in protein conformation and function that are akin to those induced by phosphorylation (71). Growing evidence supports protein Snitrosylation as an important mechanism of NO signaling (98), which is implicated in the regulation of the ryanodine receptor Ca 2 + release channel (RyR) (65, 85,244), SR Ca 2 + ATPase (SERCA) (17), LTCC (32,214), and the Kv1.5 channel (166) and the post-translational regulation of b-adrenergic signaling (170,246). Dysregulated S-nitrosylation of myocardial proteins can result not only from alterations in the expression, compartmentalization, and/or activity of NOS, but also from changes in the activity of denitrosylases such as the S-nitrosoglutathione (GSNO) metabolizing enzyme, GSNO reductase.…”

mentioning

confidence: 99%

Nitric Oxide Synthases in Heart Failure

Carnicer

Crabtree

Sivakumaran

et al. 2013

Antioxidants & Redox Signaling

150

138

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Significance: The regulation of myocardial function by constitutive nitric oxide synthases (NOS) is important for the maintenance of myocardial Ca 2+ homeostasis, relaxation and distensibility, and protection from arrhythmia and abnormal stress stimuli. However, sustained insults such as diabetes, hypertension, hemodynamic overload, and atrial fibrillation lead to dysfunctional NOS activity with superoxide produced instead of NO and worse pathophysiology. Recent Advances: Major strides in understanding the role of normal and abnormal constitutive NOS in the heart have revealed molecular targets by which NO modulates myocyte function and morphology, the role and nature of posttranslational modifications of NOS, and factors controlling nitroso-redox balance. Localized and differential signaling from NOS1 (neuronal) versus NOS3 (endothelial) isoforms are being identified, as are methods to restore NOS function in heart disease. Critical Issues: Abnormal NOS signaling plays a key role in many cardiac disorders, while targeted modulation may potentially reverse this pathogenic source of oxidative stress. Future Directions: Improvements in the clinical translation of potent modulators of NOS function/dysfunction may ultimately provide a powerful new treatment for many hearts diseases that are fueled by nitroso-redox imbalance.

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Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism

Abstract: NO inhibits the hKv1.5 current by a cGMP-dependent mechanism and by the S-nitrosylation of the hKv1.5 protein, an effect that contributes to shaping the human atrial action potentials.

Cited by 75 publications

References 46 publications

Assessment of nitric oxide signals by triiodide chemiluminescence

Assessment of nitric oxide signals by triiodide chemiluminescence

Atrial Remodeling and Atrial Fibrillation

Nitric Oxide Synthases in Heart Failure

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