The G protein coupled receptor kinase 2 plays an essential role in beta-adrenergic receptor-induced insulin resistance

Cipolletta, Ersilia; Campanile, Alfonso; Santulli, Gaetano; Sanzari, Emma; Leosco, Dario; Campiglia, Pietro; Trimarco, Bruno; Iaccarino, Guido

doi:10.1093/cvr/cvp252

Cited by 92 publications

(114 citation statements)

References 33 publications

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“…GRKs have been proposed to be modulators of cellular functions in a phosphorylation-independent manner due to their ability to interact with a variety of signaling and trafficking proteins, such as actin (79), actinin (80), tubulin (37), G␣ (36), G␤␥ (187), clathrin (225), PI3K (164), GIT (190), caveolin (36, 88), lipids, etc. GRKs have been placed in the center of regulatory processes involving cell migration (179), metabolism (50,52,254), and apoptosis (43). Further investigation is needed to address these GRK-mediated intermolecular interactions and how they link to various cellular processes.…”

Section: E Regulation Of Grksmentioning

confidence: 99%

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

126

152

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G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent β-arrestin-mediated mechanisms including phosphorylation, internalization, and either receptor degradation or resensitization. The seven-member GRK family varies in their structural composition, cellular localization, function, and mechanism of action (see sect. II). Here, we focus our attention on GRKs in particular canonical and novel roles of the GRKs found in the cardiovascular system (see sects. III and IV). Paramount to overall cardiac function is GPCR-mediated signaling provided by the adrenergic system. Overstimulation of the adrenergic system has been highly implicated in various etiologies of cardiovascular disease including hypertension and heart failure. GRKs acting downstream of heightened adrenergic signaling appear to be key players in cardiac homeostasis and disease progression, and herein we review the current data on GRKs related to cardiac disease and discuss their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure.

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Section: E Regulation Of Grksmentioning

confidence: 99%

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

126

152

View full text Add to dashboard Cite

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“…However, recent evidence has shown that GRK2 can restrain signaling via direct interaction with downstream intracellular kinases, including Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase, and p38, leading to modulation of their activity (Liu et al, 2005;Jimenez-Sainz et al, 2006). Furthermore, GRK2 can also regulate signaling mediated by other membrane receptor families, such as tyrosine kinase receptors for insulin, insulin-like growth factor 1, platelet-derived growth factor, and epidermal growth factor (Kim et al, 2003;Cipolletta et al, 2009). Thus, it should be stressed that the cellular role of GRK2 is not limited to promoting b-arrestin binding to activated GPCRs.…”

Section: Introductionmentioning

confidence: 99%

Tonic Inhibition by G Protein–Coupled Receptor Kinase 2 of Akt/Endothelial Nitric-Oxide Synthase Signaling in Human Vascular Endothelial Cells under Conditions of Hyperglycemia with High Insulin Levels

Taguchi

Sakata

Ohashi

et al. 2014

J Pharmacol Exp Ther

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G protein-coupled receptor kinase 2 (GRK2) participates together with b-arrestins in the regulation of G protein-coupled receptor signaling, but emerging evidence suggests that GRK2 can interact with a growing number of proteins involved in signaling mediated by other membrane receptor families under various pathologic conditions. We tested the hypothesis that GRK2 may be an important contributor to vascular endothelial dysfunction in diabetes. Human umbilical venous endothelial cells (HUVECs) were exposed to high glucose and high insulin (HG/HI) to mimic insulin-resistant diabetic conditions. GRK2 expression and membrane translocation were up-regulated under HG/HI conditions. HG/HI did not modify activation of Akt or endothelial nitric-oxide synthase (eNOS), but GRK2 inhibitor or small interfering RNA (siRNA) resulted in an increase in Akt and eNOS activation in HUVECs exposed to HG/HI. Extracellular signal-regulated kinase 1/2 (ERK1/2) activation was increased after exposure to HG/HI, which was prevented by GRK2 inhibitor or siRNA. ERK1/ 2-mediated GRK2 phosphorylation at Ser-670 confirmed that ERK1/2 participated in a negative feedback regulatory loop. In human embryonic kidney 293T cells that overexpressed GRK2, Akt activity was unchanged, whereas ERK1/2 activity was raised. The effect of GRK inhibitor treatment on Akt/eNOS signaling was associated with membrane translocation of b-arrestin 2. The experiments with b-arrestin 2 siRNA showed that b-arrestin 2 may act as a positive modulator of Akt/eNOS signaling. Our studies reveal that GRK2, which is up-regulated by HG/HI, leads to a tonic inhibition of the insulin Akt/eNOS pathway in endothelial cells. We provide new insights into the pathogenesis of diabetes-associated vascular endothelial dysfunction.

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“…59 Insulin administration increases GRK2 cellular levels within 15-30 minutes. 61 Insulin-like growth factor-1 induces GRK2 cellular accumulation by inhibiting mouse double minute 2 (Mdm2), which is responsible for kinase ubiquitination and degradation. 62 Chronic insulin treatments are characterized by increased GRK2 levels.…”

Section: Grk2 Functions and Involvement In Human Diseasesmentioning

confidence: 99%

“…In addition to peptides derived from the first intracellular loop of the hamster β 2 -AR, small peptides derived from GRK2/3 KD were tested in animal models of diabetes to investigate the treatments for type 2 diabetes 113. GRK2 inhibition can lead to the restoration of signaling pathways involved in glucose homeostasis control 59,61,63,114. Acylated glycine derivatives of short peptides, such as myristyl…”

mentioning

confidence: 99%

G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitors: Current Trends and Future Perspectives

et al. 2016

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G-protein-coupled receptor kinase 2 (GRK2) is a G-protein-coupled receptor kinase that is ubiquitously expressed in many tissues and regulates various intracellular mechanisms. The up- or down-regulation of GRK2 correlates with several pathological disorders. GRK2 plays an important role in the maintenance of heart structure and function; thus, this kinase is involved in many cardiovascular diseases. GRK2 up-regulation can worsen cardiac ischemia; furthermore, increased kinase levels occur during the early stages of heart failure and in hypertensive subjects. GRK2 up-regulation can lead to changes in the insulin signaling cascade, which can translate to insulin resistance. Increased GRK2 levels also correlate with the degree of cognitive impairment that is typically observed in Alzheimer's disease. This article reviews the most potent and selective GRK2 inhibitors that have been developed. We focus on their mechanism of action, inhibition profile, and structure-activity relationships to provide insight into the further development of GRK2 inhibitors as drug candidates.

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The G protein coupled receptor kinase 2 plays an essential role in beta-adrenergic receptor-induced insulin resistance

Abstract: Our results suggest that GRK2 mediates adrenergic IRES and that inhibition of GRK2 activity leads to increased Ins sensitivity both in cells and in animal model of IRES.

Cited by 92 publications

References 33 publications

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Tonic Inhibition by G Protein–Coupled Receptor Kinase 2 of Akt/Endothelial Nitric-Oxide Synthase Signaling in Human Vascular Endothelial Cells under Conditions of Hyperglycemia with High Insulin Levels

G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitors: Current Trends and Future Perspectives

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