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 beta-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 beta-arrestins (beta-Arr) that modulate beta-AR signal termination via receptor desensitization and downregulation. GRK2 and beta-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 beta-Arrs.

Automated summary

Cardiac diseases, especially heart failure, are the leading cause of morbidity and mortality globally. The loss of beta-adrenoceptor-mediated inotropic reserve and the elevated activities of G protein-coupled receptor kinases and beta-arrestins after heart injury/stress play significant roles in heart failure. Nitric oxide produced by NO synthase enzymes modulates GPCR regulators profoundly through S-nitrosylation, independent of its canonical signaling pathway.