Increased Acute Inflammation, Leukotriene B4-Induced Chemotaxis, and Signaling in Mice Deficient for G Protein-Coupled Receptor Kinase 6

Kavelaars, Annemieke; Vroon, Anne; Raatgever, Roel; Fong, Alan M.; Premont, Richard T.; Patel, Dhavalkumar D.; Lefkowitz, Robert J.; Heijnen, Cobi J.

doi:10.4049/jimmunol.171.11.6128

Cited by 65 publications

(56 citation statements)

References 31 publications

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“…Important to note are the studies reporting the involvement of GRK6 in lymphocyte chemotaxis and inflammation (76,124). Lymphocytes from GRK6 KO mice possess impaired chemotactic ability to respond to CXCL12, which is more pronounced in T cells than B cells (76).…”

Section: B Grk4 and Grk6 In Hypertensionmentioning

confidence: 99%

“…Polymorphonuclear neutrophils (PMN) are involved in defense against infection, and leukotriene (LT) B 4 is one of the most potent chemoattractants of PMN. Studies in GRK6 KO mice revealed increased PMN response towards LTB 4 and stromal cell-derived factor 1 (SDF-1) (124). Loss of GRK6 in mice reduces and enhances chemotaxis in lymphocytes and PMN, respectively, suggesting a cell-specific role of GRK6.…”

Section: B Grk4 and Grk6 In Hypertensionmentioning

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

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: B Grk4 and Grk6 In Hypertensionmentioning

confidence: 99%

Section: B Grk4 and Grk6 In Hypertensionmentioning

confidence: 99%

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

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

127

152

View full text Add to dashboard Cite

show abstract

“…It is well established that elimination of GRKs or of their target sites in a given receptor can have major effects on the levels and dynamics of heterotrimeric G-protein signaling and second messenger production in response to GPCR activation (Kavelaars et al, 2003;Peppel et al, 1997;Ren et al, 2005;Violin et al, 2006;Wang et al, 2009). Given the central role of Pka in Hh signaling, cAMP misregulation could have significant effects on target gene expression.…”

Section: Elimination Of Gprk2 Lowers Basal Cellular Camp Levelsmentioning

confidence: 99%

Drosophila G-protein-coupled receptor kinase 2 regulates cAMP-dependent Hedgehog signaling

2012

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G-protein-coupled receptor kinases (GRKs) play a conserved role in Hedgehog (Hh) signaling. In several systems, GRKs are required for efficient Hh target gene expression. Their principal target appears to be Smoothened (Smo), the intracellular signal-generating component of the pathway and a member of the G-protein-coupled receptor (GPCR) protein family. In Drosophila, a GRK called Gprk2 is needed for internalization and downregulation of activated Smo, consistent with the typical role of these kinases in negatively regulating GPCRs. However, Hh target gene activation is strongly impaired in gprk2 mutant flies, indicating that Gprk2 must also positively regulate Hh signaling at some level. To investigate its function in signaling, we analyzed several different readouts of Hh pathway activity in animals or cells lacking Gprk2. Surprisingly, although target gene expression was impaired, Smo-dependent activation of downstream components of the signaling pathway was increased in the absence of Gprk2. This suggests that Gprk2 does indeed play a role in terminating Smo signaling. However, loss of Gprk2 resulted in a decrease in cellular cAMP concentrations to a level that was limiting for Hh target gene activation. Normal expression of target genes was restored in gprk2 mutants by stimulating cAMP production or activating the cAMP-dependent Protein kinase A (Pka). Our results suggest that direct regulation of Smo by Gprk2 is not absolutely required for Hh target gene expression. Gprk2 is important for normal cAMP regulation, and thus has an indirect effect on the activity of Pka-regulated components of the Hh pathway, including Smo itself.

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“…16 Prolonged LTB 4 stimulation was reported to desensitize human neutrophils for chemotaxis and calcium influx, through the phosphorylation, by GRK6, of the LTB 4 receptor. 36 Macrophage inflammatory protein-2 was shown to induce, in vitro, expression of GRK2 and GRK5 in blood neutrophils. 17 Studies on CXCR1 and CXCR2 functionality showed that high concentrations of IL-8 (CXCL8) decrease migratory responses.…”

Section: Grk and Neutrophil Chemotaxis Failure In Sepsis 2911mentioning

confidence: 99%

Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation

Arraes

Freitas

Silva

et al. 2006

Blood

138

106

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The deregulation of inflammatory response during sepsis seems to reflect the overproduction of mediators, which suppress leukocyte functions. We investigated the intracellular mechanisms underlying the inability of neutrophils from severe septic patients to migrate toward chemoattractants. Patients IntroductionSepsis is a complex clinical syndrome resulting from a damaging host response to infection. 1 In the United States, more than 700 000 patients per year develop sepsis, with mortality rates reported to vary between 30% and 70%, despite the best available supportive care. 2 Polymorphonuclear neutrophils (PMNs) play the first line in the host defense against microorganisms, being recruited to the inflammatory sites by chemoattractants such as leukotriene B 4 (LTB 4 ) and chemokines. 3,4 Once emigrated, these leukocytes are able to phagocytose and to generate large amounts of reactive oxygen and nitrogen species, such as hydrogen peroxide and nitric oxide, which are crucial products for the microbicidal activity of these cells. 5,6 As neutrophils appear to play a crucial role in the control of the infectious process, one can hypothesize that a deficient migratory ability of neutrophils may aggravate infections. Indeed, impairment of neutrophil migration has been reported in leukemia, 7 diabetes, 8 and AIDS, 9 diseases associated with high susceptibility to infection. Furthermore, previous studies from our group showed that failure of neutrophil migration is observed in severe sepsis induced by cecal ligation and puncture and Staphylococcus aureus administration. 10,11 In these lethal models, failure of neutrophil migration to the site of infection was accompanied by increased numbers of bacteria in the peritoneal fluid and blood. Conversely, in sublethal infection in which massive neutrophil migration was observed, bacterial infection was restricted to the peritoneal cavity, and the animals exhibited a low mortality rate. 10,11 More recently, we have also reported that blood neutrophils obtained from patients with sepsis failed to respond in vitro to the chemotactic stimuli FMLP and LTB 4 . This unresponsiveness was directly associated to a poor prognosis. 12 Evidence from literature suggests that the high levels of circulating cytokines/chemokines observed in severe sepsis may mediate the impairment of neutrophil migration, in addition to being involved in the deleterious physiopathologic findings of the disease, such as coagulation disorders, cardiovascular collapse, and organ failure. 13 The intravenous administration of tumor necrosis factor-␣ (TNF-␣) or interleukin-8 (IL-8) inhibited neutrophil migration to mouse peritoneal cavity and anti-TNF-␣ antibody partially prevented the inhibition of neutrophil migration in endotoxemia model. 14 However, the molecular mechanisms involved in the reduced ability of neutrophils to migrate during sepsis were not completely clarified.Independent of their chemical nature, most chemoattractants exert their action via binding to specific G protein-coupled receptors (GP...

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Increased Acute Inflammation, Leukotriene B4-Induced Chemotaxis, and Signaling in Mice Deficient for G Protein-Coupled Receptor Kinase 6

Cited by 65 publications

References 31 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

Drosophila G-protein-coupled receptor kinase 2 regulates cAMP-dependent Hedgehog signaling

Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation

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