GRK2 as negative modulator of NO bioavailability: Implications for cardiovascular disease

Abstract

Nitric oxide (NO), initially identified as endothelium-derived relaxing factor (EDRF), is a gaso-transmitter with important regulatory roles in the cardiovascular, nervous and immune systems. In the former, this diatomic molecule and free radical gas controls vascular tone and cardiac mechanics, among others. In the cardiovascular system, it is now understood that β-adrenergic receptor (βAR) activation is a key modulator of NO generation. Therefore, it is not surprising that the up-regulation of G protein-coupled receptor kinases (GRKs), in particular GRK2, that restrains βAR activity contributes to impaired cardiovascular functions via alteration of NO bioavailability. This review, will explore the specific interrelation between βARs, GRK2 and NO in the cardiovascular system and their inter-relationship for the pathogenesis of the onset of disease. Last, we will update the readers on the current status of GRK2 inhibitors as a potential therapeutic strategy for heart failure with an emphasis on their ability of rescuing NO bioavailability.

Keywords: Cardiovascular system; G protein-coupled receptor kinase; Nitric oxide; β-adrenergic receptor.

Figure 1. General Mechanism of protein S-nitrosylation

S-nitrosylation take place either via direct binding of NO to sulfhydryl (-SH) groups present in a specific cysteine residue of a protein (protein A becomes SNO-protein A) or through the interaction with trans-S-nitrosylases (SNO-protein B), which directly transfers S-nitrosothiols to another SH-group of a recipient protein (protein A) in a process called S-transnitrosation.

Figure 2. Mechanism of GRK2 S-nitrosylation

Catecholamine (CA) mediated activation of β2-adrenergic receptor (β₂AR) lead to Akt and endothelial nitric oxide synthase (eNOS) activation. eNOS converts the amino acid L-arginine to form L-citrulline and the free radical NO. The NO then reacts with glutathione (GSH) to form S-nitrosoglutathione (GSNO). GSNO transfers its NO group to the sulfhydryl (-SH) group of the Cysteine in position 340 of GRK2 protein to form S-nitrosothiol-GRK2 (SNO-GRK2). Following this modification GRK2 loses its ability to phosphorylate and desensitize/downregulate the β₂AR leading to an enhancement of its signaling pathway.

Figure 3. Direct and indirect mechanisms implicated in β₁AR-blocker-mediated NO generation

β₁AR-blockers are usually helpful in the treatment of conditions characterized by increased sympathetic nervous system activation. In fact, these class of drugs prevent catecholamine mediated β₁AR-hyperstimulation and abolish the up-regulation of GRK2. This lead to a significant reduction of GRK2 mediated inhibition of Insulin signaling with a consequent increase in Akt and endothelial nitric oxide synthase (eNOS) activation. Moreover, these drugs can directly (agonism) or indirectly activate (conveying catecholamines) other adrenergic receptors such as the β₃AR that can induce, via Gs or Gi coupling, both eNOS and neuronal NOS (nNOS) activation, giving rise to NO.