Nitric Oxide and S-Nitrosylation in Cardiac Regulation: G Protein-Coupled Receptor Kinase-2 and β-Arrestins as Targets

Cardiac diseases including heart failure (HF), are the leading cause of morbidity and mortality globally. Among the prominent characteristics of HF is the loss of β-adrenoceptor (AR)-mediated inotropic reserve. This is primarily due to the derangements in myocardial regulatory signaling proteins, G protein-coupled receptor (GPCR) kinases (GRKs) and β-arrestins (β-Arr) that modulate β-AR signal termination via receptor desensitization and downregulation. GRK2 and β-Arr2 activities are elevated in the heart after injury/stress and participate in HF through receptor inactivation. These GPCR regulators are modulated profoundly by nitric oxide (NO) produced by NO synthase (NOS) enzymes through S-nitrosylation due to receptor-coupled NO generation. S-nitrosylation, which is NO-mediated modification of protein cysteine residues to generate an S-nitrosothiol (SNO), mediates many effects of NO independently from its canonical guanylyl cyclase/cGMP/protein kinase G signaling. Herein, we review the knowledge on the NO system in the heart and S-nitrosylation-dependent modifications of myocardial GPCR signaling components GRKs and β-Arrs.

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Synergistic Regulation of m2 Muscarinic Acetylcholine Receptor Desensitization and Sequestration by G Protein-coupled Receptor Kinase-2 and β-Arrestin-1

Journal of Biological Chemistry ◽

10.1074/jbc.272.30.18882 ◽

1997 ◽

Vol 272 (30) ◽

pp. 18882-18890 ◽

Cited By ~ 59

Author(s):

Michael L. Schlador ◽

Neil M. Nathanson

Keyword(s):

G Protein ◽

Acetylcholine Receptor ◽

Muscarinic Acetylcholine Receptor ◽

Receptor Desensitization ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

Muscarinic Acetylcholine ◽

Synergistic Regulation ◽

G Protein Coupled

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Selective Reduction in A2 Adenosine Receptor Desensitization Following Antisense-Induced Suppression of G Protein-Coupled Receptor Kinase 2 Expression

Journal of Neurochemistry ◽

10.1046/j.1471-4159.1999.0731781.x ◽

2002 ◽

Vol 73 (5) ◽

pp. 1781-1789 ◽

Cited By ~ 5

Keyword(s):

G Protein ◽

Adenosine Receptor ◽

Selective Reduction ◽

Receptor Desensitization ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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β-Arrestins: Multifunctional Cellular Mediators

Physiology ◽

10.1152/physiol.00042.2007 ◽

2008 ◽

Vol 23 (1) ◽

pp. 17-22 ◽

Cited By ~ 26

Author(s):

Liza Barki-Harrington ◽

Howard A. Rockman

Keyword(s):

G Protein ◽

Signaling Proteins ◽

Receptor Desensitization ◽

Receptor Signaling ◽

G Protein Coupled Receptor ◽

Cellular Mediators ◽

The Many ◽

G Protein Coupled

Initially thought to play a role only in G-protein-coupled receptor desensitization, β-arrestins are ascribed with new roles such as scaffolding and signaling proteins by their own right. This review explores the many functions of β-arrestins, with an emphasis on their recently identified role as regulators of receptor signaling.

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Cardiac hyporesponsiveness in severe sepsis is associated with nitric oxide-dependent activation of G protein receptor kinase

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00052.2016 ◽

2017 ◽

Vol 313 (1) ◽

pp. H149-H163 ◽

Cited By ~ 11

Author(s):

Daniela Dal-Secco ◽

Silvia DalBó ◽

Natalia E. S. Lautherbach ◽

Fábio N. Gava ◽

Mara R. N. Celes ◽

...

Keyword(s):

Nitric Oxide ◽

G Protein ◽

Cardiac Dysfunction ◽

Therapeutic Target ◽

Adrenergic Receptor ◽

Receptor Density ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

Potential Therapeutic Target ◽

G Protein Coupled

G protein-coupled receptor kinase isoform 2 (GRK2) has a critical role in physiological and pharmacological responses to endogenous and exogenous substances. Sepsis causes an important cardiovascular dysfunction in which nitric oxide (NO) has a relevant role. The present study aimed to assess the putative effect of inducible NO synthase (NOS2)-derived NO on the activity of GRK2 in the context of septic cardiac dysfunction. C57BL/6 mice were submitted to severe septic injury by cecal ligation and puncture (CLP). Heart function was assessed by isolated and perfused heart, echocardiography, and β-adrenergic receptor binding. GRK2 was determined by immunofluorescence and Western blot analysis in the heart and isolated cardiac myocytes. Sepsis increased NOS2 expression in the heart, increased plasma nitrite + nitrate levels, and reduced isoproterenol-induced isolated ventricle contraction, whole heart tension development, and β-adrenergic receptor density. Treatment with 1400W or with GRK2 inhibitor prevented CLP-induced cardiac hyporesponsiveness 12 and 24 h after CLP. Increased labeling of total and phosphorylated GRK2 was detected in hearts after CLP. With treatment of 1400W or in hearts taken from septic NOS2 knockout mice, the activation of GRK2 was reduced. 1400W or GRK2 inhibitor reduced mortality, improved echocardiographic cardiac parameters, and prevented organ damage. Therefore, during sepsis, NOS2-derived NO increases GRK2, which leads to a reduction in β-adrenergic receptor density, contributing to the heart dysfunction. Isolated cardiac myocyte data indicate that NO acts through the soluble guanylyl cyclase/cGMP/PKG pathway. GRK2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction. NEW & NOTEWORTHY The main novelty presented here is to show that septic shock induces cardiac hyporesponsiveness to isoproterenol by a mechanism dependent on nitric oxide and mediated by G protein-coupled receptor kinase isoform 2. Therefore, G protein-coupled receptor kinase isoform 2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction.

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