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.
Highlights
Gprotein-coupled receptors (GPCRs) play important roles in the regulation of cardiac function
GPCR signaling have been shown to be profoundly affected by S-nitrosylation
GRK2 is is shown to be subjected to SNO regulation by both eNOS and iNOS, whereas β-Arr2 is shown to be subjected to SNO regulation by both eNOS and iNOS, whereas β-Arr2 is SS-nitrosylated by distinct NO synthase (NOS) isoforms resulting in various consequences
Summary
Gprotein-coupled receptors (GPCRs) play important roles in the regulation of cardiac function. GPCRs are phosphorylated by GPCR kinases (GRKs) and thereafter associate with β-arrestins (β-Arr), which regulate receptor desensitization and internalization Activities of these regulatory molecules are augmented after stress/injury and result in excessive signal uncoupling and receptor desensitization which contribute to pathogenesis [1,2]. Important GPCR molecules in the heart including β-adrenoceptors (βARs), GRKs and β-Arr can be modulated by S-nitrosylation that is triggered by NOS-mediated generation of NO [11,12,13,14]. Three forms of NOS catalyzes the synthesis of NO, NOS1 (neuronal or nNOS), NOS2 (inducible or iNOS) and NOS3 (endothelial or eNOS) [9] They convert L-arginine and oxygen to L-citrulline and NO in the presence of nicotinamide-adenine-dinucleotide phosphate (NADPH) as co-substrate and tetrahydrobiopterin (BH4 ), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) as cofactors [9,22]. Translocation of NOS to another compartment with a different oxygen levels alter its activity [18]
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