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

Abstract

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.

Keywords: GRK2; S-nitrosylation; nitric oxide; β-arrestins.

Figure 1

Schematic representation depicting the current understanding of the interaction between β-AR-signaling and GRK2 S-nitrosylation. β-AR, β-adrenergic receptor; G-protein subtypes (Gs or Gi); GRK2, G protein-coupled receptor kinase 2; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; nNOS, neuronal nitric oxide synthase. Green arrow is used to indicate a stimulatory mechanism involved while red bar-headed line indicates an inhibitory mechanism.

Figure 2

Differential regulation of GRK subtypes via S-nitrosylation. GRK, G protein-coupled receptor kinase; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; nNOS, neuronal nitric oxide synthase. Green arrow is used to indicate a stimulatory mechanism involved.

Figure 3

Differential regulation of β-arrestins via S-nitrosylation. β-Arr, β-arrestin; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; nNOS, neuronal nitric oxide synthase; iNOS, inhibitory nitric oxide synthase. Green arrow is used to indicate a stimulatory mechanism involved.