LAUSR

Recently, many reports have indicated that G protein, G protein-coupled receptors (GPCR), and related enzymes play an important role in cardiovascular disease. GPCR are also known as seven-(pass)-transmembrane domain receptors that are coupled with G protein. GPCR kinases (GRK) are a family of protein kinases that regulate the activity of GPCR by phosphorylating their intracellular domains after their associated G proteins have been released and activated. Basically, the sustained stimulation of β-adrenergic receptors (β-AR) that transmit information via G protein leads to β-AR desensitization and a reduced response to β-adrenergic agonists. The desensitization is composed of two phases: an early desensitization occurring within a few seconds to several minutes, and a long-term desensitization occurring after more than 1 h. In early desensitization, there is uncoupling of the receptor and G protein and disappearance of the receptor from the cell surface (sequestration). In long-term desensitization, the receptor protein is downregulated itself. In early desensitization, the receptor protein is phosphorylated by GRK or cAMP-dependent protein kinase A (PKA). Although PKA activation without receptor stimulation can phosphorylate the receptor, GRK phosphorylates only receptors activated by agonists. Homologous desensitization by GRK is considered to be an important mechanism to prevent an excessive cellular response to agonists. GRK has seven subtypes, and GRK2, which is also known as β-AR kinase (βARK) 1, is a member of the GRK family of serine/threonine protein kinases that phosphorylate and desensitize GPCR (such as adrenergic and muscarinic receptors). Upregulation or downregulation of GRK2 may occur in several pathophysiological disorders, and these changes can exacerbate cardiovascular and metabolic diseases [1, 2]. The signaling of GRK2 in the cardiomyocytes is shown in Fig. 1. GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation, and GRK2 inhibitors can improve glucose homeostasis and the insulin response and lead to enhanced insulin sensitivity [2, 3]. It has also been reported that GRK2 is increased and signal transduction is suppressed in diabetes, because GRK2 antagonizes β-arrestin 2, which is a downstream target protein [4]. Increased levels of GRK2 can decrease insulin signaling in several cell types and tissues [2]. These findings suggest that GRK2 plays an important role in the pathogenesis and deterioration of diabetes and metabolic syndrome. In addition, insulin stimulates endothelial nitric oxide synthase (eNOS) activity by Akt activation, leading to eNOS phosphorylation, NO production, and vasorelaxation. Furthermore, impaired insulin-mediated Akt/eNOSdependent signaling was recognized in diabetic murine models [4, 5]. Therefore, GRK2 promotes diabetic endothelial dysfunction via suppression of the insulin-stimulated Akt/eNOS/NO signaling pathway, and inhibition of GRK2 expression can improve endothelial dysfunction by restoring glucose homeostasis [4–6]. The inhibition of the Akt/eNOS pathway by GRK2 in vascular endothelial cells may cause attenuated vasorelaxation. Therefore, GRK2 in endothelial cells may play an important role in abnormalities of the Akt/eNOS signal during the development of diabetic vasculopathy. Recently, many studies have reported a relationship between GRK2 and hypertension. A link between Gβ3 C825T polymorphism and hypertension was reported in population-based and case-control studies in different ethnicities in humans. Because Gβ3 C825T polymorphism impairs the function of Gβ3 to target GRK2 ubiquitination, the loss of Gβ3 function minimizes GRK2 ubiquitination and stabilizes GRK2 [7]. In basic studies, genetic knockdown of GRK2 using a small hairpin RNA resulted in spontaneous hypertension and altered vascular GPCR * Jun-ichi Oyama [email protected]