Regulation of Nuclear Factor κB (NF-κB) in the Nucleus of Cardiomyocytes by G Protein-coupled Receptor Kinase 5 (GRK5)

Islam, Kazi Nazrul; Bae, Jang‐Whan; Gao, Erhe; Koch, Walter J.

doi:10.1074/jbc.m113.529347

Cited by 47 publications

(43 citation statements)

References 37 publications

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“…Activation of NF〉 led to binding of p50 and p65 to the GRK5 promoter and subsequent increase in GRK5 expression after hypertrophic stimuli (115). Conversely to the mechanism proposed in FIGURE 5A, overexpression of GRK5 increased levels of p50 and p65, and silencing of GRK5 led to decreased levels of p50 and p65 and loss of NF〉 DNA binding activity (114). A schematic of the latter mechanism is shown in FIGURE 5B.…”

Section: A Grk5 and Its Role In Pathological Cardiac Hypertrophy Andmentioning

confidence: 71%

“…Further studies have also confirmed GRK5 as a mediator of NF〉 signaling in mammals, with potential implications in cardiac hypertrophy and other cardiovascular pathologies, although the mechanism of action is still not fully understood (114,170,232). NF〉 is a highly regulated dimeric transcription factor present as heterodimers (p50:p65) or homodimers (p50:p50 or p65:p65) (87).…”

Section: A Grk5 and Its Role In Pathological Cardiac Hypertrophy Andmentioning

confidence: 99%

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

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

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127

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: A Grk5 and Its Role In Pathological Cardiac Hypertrophy Andmentioning

confidence: 71%

Section: A Grk5 and Its Role In Pathological Cardiac Hypertrophy Andmentioning

confidence: 99%

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

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

Self Cite

127

152

View full text Add to dashboard Cite

show abstract

“…However, it is also possible that decreased NF-B activation could be a result of the previously demonstrated role of GRK5 in NF-B signaling (11,38). GRK5 has been shown to regulate NF-B signaling positively (macrophages) (10) or negatively (endothelial cells) (38) and to modulate inflammatory response depending on the cell type involved (39). We have shown that in endotoxemia (20) and polymicrobial sepsis (19), GRK5 mediates cytokine production and GRK5 KO mice exhibit an attenuated inflammatory response.…”

Section: Discussionmentioning

confidence: 91%

Bacterial Dose-Dependent Role of G Protein-Coupled Receptor Kinase 5 in Escherichia coli-Induced Pneumonia

et al. 2016

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c G protein-coupled receptor kinase 5 (GRK5) is a serine/threonine kinase previously shown to mediate polymicrobial sepsis-induced inflammation. The goal of the present study was to examine the role of GRK5 in monomicrobial pulmonary infection by using an intratracheal Escherichia coli infection model of pneumonia. We used sublethal and lethal doses of E. coli to examine the mechanistic differences between low-grade and high-grade inflammation induced by E. coli infection. With a sublethal dose of E. coli, GRK5 knockout (KO) mice exhibited higher plasma CXCL1/KC levels and enhanced lung neutrophil recruitment early after infection, and lower bacterial loads, than wild-type (WT) mice. The inflammatory response was also diminished, and resolution of inflammation advanced, in the lungs of GRK5 KO mice. In contrast to the reduced bacterial loads in GRK5 KO mice following a sublethal dose, at a lethal dose of E. coli, the bacterial burdens remained high in GRK5 KO mice relative to those in WT mice. This occurred in spite of enhanced plasma CXCL1 levels as well as neutrophil recruitment in the KO mice. But the recruited neutrophils (following high-dose infection) exhibited decreased CD11b expression and reduced reactive oxygen species production, suggesting decreased neutrophil activation or increased neutrophil exhaustion in the GRK5 KO mice. In agreement with the increased bacterial burden, KO mice showed poorer survival than WT mice following E. coli infection at a lethal dose. Overall, our data suggest that GRK5 negatively regulates CXCL1/KC levels during bacterial pneumonia but that the role of GRK5 in the clinical outcome in this model is dependent on the bacterial dose.

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“…Wherein mice generated by the Lefkowitz group (Wu et al, 2012) found that endothelial GRK5 stabilized IκBα similar to earlier studies by Sorriento et al (Daniela Sorriento et al, 2008), studies done in macrophages using a different GRK5 knock out mice did not show any role for GRK5 in IκBα phosphorylation or p65 translocation. More recent studies using mice from the Lefkowitz group, however, have shown that GRK5 positively regulates the NFκB pathway in cardiomyocytes (Islam, Bae, Gao, & Koch, 2013). It is unclear the exact reasoning behind these discrepancies in GRK5 behavior but it has also been shown that GRK5 itself can be regulated by the NFκB pathway, generating a potential positive feedback loop between GRK5 and NFκB (Islam & Koch, 2012).…”

Section: Grks In Inflammatory Signaling and Diseasementioning

confidence: 99%

G Protein-Coupled Receptor Kinases in the Inflammatory Response and Signaling

Steury

McCabe

Parameswaran

2017

Advances in Immunology

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G-protein coupled receptor kinases (GRKs) are serine/threonine kinases that regulate a large and diverse class of G-protein coupled receptors (GPCRs). Through GRK phosphorylation and β-arrestin recruitment GPCRs are desensitized and their signal terminated. Recent work on these kinases has expanded their role from canonical GPCR regulation to include non-canonical regulation of non-GPCR and non-receptor substrates through phosphorylation as well as via scaffolding functions. Due to these and other regulatory roles, GRKs have been shown to play a critical role in the outcome of a variety of physiological and pathophysiological processes including chemotaxis, signaling, migration, inflammatory gene expression, etc. This diverse set of functions for these proteins makes them popular targets for therapeutics. Role for these kinases in inflammation and inflammatory disease is an evolving area of research currently pursued in many laboratories. In this review, we describe the current state of knowledge on various GRKs pertaining to their role in inflammation and inflammatory diseases.

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Regulation of Nuclear Factor κB (NF-κB) in the Nucleus of Cardiomyocytes by G Protein-coupled Receptor Kinase 5 (GRK5)

Cited by 47 publications

References 37 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

Bacterial Dose-Dependent Role of G Protein-Coupled Receptor Kinase 5 in Escherichia coli-Induced Pneumonia

G Protein-Coupled Receptor Kinases in the Inflammatory Response and Signaling

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