Hypoxia/Ischemia Modulates G Protein–Coupled Receptor Kinase 2 and β-Arrestin-1 Levels in the Neonatal Rat Brain

Lombardi, Maria Stella; Tweel, Evelyn van den; Kavelaars, Annemieke; Groenendaal, Floris; Bel, Frank van; Heijnen, Cobi J.

doi:10.1161/01.str.0000121644.82596.7e

Cited by 44 publications

(28 citation statements)

References 34 publications

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“…Interestingly, neonatal HI-induced brain damage is associated with a decrease in cerebral GRK2 protein expression before damage becomes apparent (Lombardi et al, 2004). These data suggest that decreased GRK2 may contribute to the pathophysiological process leading to HI-induced brain damage.…”

Section: Introductionmentioning

confidence: 80%

Low Endogenous G-Protein-Coupled Receptor Kinase 2 Sensitizes the Immature Brain to Hypoxia–Ischemia-Induced Gray and White Matter Damage

Nijboer¹,

Kavelaars²,

Vroon³

et al. 2008

J. Neurosci.

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Hypoxic-ischemic brain injury is regulated in part by neurotransmitter and chemokine signaling via G-protein-coupled receptors (GPCRs). GPCR-kinase 2 (GRK2) protects these receptors against overstimulation by inducing desensitization. Neonatal hypoxic-ischemic brain damage is preceded by a reduction in cerebral GRK2 expression. We determined the functional importance of GRK2 in hypoxic-ischemic brain damage.Nine-day-old wild-type and GRK2 ϩ/Ϫ mice with a ϳ50% reduction in GRK2 protein were exposed to unilateral carotid artery occlusion and hypoxia. In GRK2 ϩ/Ϫ animals, gray and white matter damage was aggravated at 3 weeks after hypoxia-ischemia. In addition, cerebral neutrophil infiltration was increased in GRK2 ϩ/Ϫ animals. Neutrophil depletion reduced brain damage, but neuronal loss was still more pronounced in GRK2 ϩ/Ϫ animals. Onset of neuronal loss was advanced in GRK2 ϩ/Ϫ animals regardless of neutrophil depletion. White matter injury was advanced in GRK2 ϩ/Ϫ animals and was not affected by neutrophil depletion. Activation/infiltration of microglia/macrophages was stronger in GRK2 ϩ/Ϫ brains but only occurred 24 h after hypoxia-ischemia and is therefore not the primary cause of increased damage. During hypoxia, cerebral blood flow was reduced to the same extent in both genotypes. In vitro, GRK2 ϩ/Ϫ hippocampal slices and cerebellar granular neurons were more sensitive to glutamate-induced death.We propose the novel concept that the kinase GRK2 regulates onset and magnitude of hypoxic-ischemic brain damage. Increased gray and white matter damage in GRK2 ϩ/Ϫ animals was not dependent on infiltrating neutrophils and occurred before microglia/macrophage activation was detected. Collectively, our data suggest that cerebral GRK2 has an important endogenous neuroprotective role in ischemic cerebral damage.

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Section: Introductionmentioning

confidence: 80%

Low Endogenous G-Protein-Coupled Receptor Kinase 2 Sensitizes the Immature Brain to Hypoxia–Ischemia-Induced Gray and White Matter Damage

Nijboer¹,

Kavelaars²,

Vroon³

et al. 2008

J. Neurosci.

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“…Interestingly, in several pathophysiological conditions such as cerebral hypoxia/ischemia (36) or in the hypothyroid liver (37), GRK2 downregulation (mainly taking place at the protein level) is accompanied by an up-regulation of ␤-arrestin expression. An inverse correlation between GRK2 and arrestin protein levels has also been described in other hypothyroid organs (37) and in macrophages sustainedly stimulated through Toll-like receptors (38).…”

Section: Discussionmentioning

confidence: 99%

Multiple Scaffolding Functions of β-Arrestins in the Degradation of G Protein-coupled Receptor Kinase 2

Salcedo¹,

Mayor

Penela

2011

Journal of Biological Chemistry

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G protein-coupled receptor kinase 2 (GRK2) plays a fundamental role in the regulation of G protein-coupled receptors (GPCRs), and changes in GRK2 expression levels can have an important impact on cell functions. GRK2 is known to be degraded by the proteasome pathway. We have shown previously that ␤-arrestins participate in enhanced kinase turnover upon GPCR stimulation by facilitating GRK2 phosphorylation by c-Src or by MAPK or by recruiting the Mdm2 E3 ubiquitin ligase to the receptor complex. In this report, we have investigated how such diverse ␤-arrestin scaffold functions are integrated to modulate GRK2 degradation. Interestingly, we found that in the absence of GPCR activation, ␤-arrestins do not perform an adaptor role for GRK2/Mdm2 association, but rather compete with GRK2 for direct Mdm2 binding to regulate basal kinase turnover. Upon agonist stimulation, ␤-arrestins-mediated phosphorylation of GRK2 at serine 670 by MAPK facilitates Mdm2-mediated GRK2 degradation, whereas c-Src-dependent phosphorylation would support the action of an undetermined ␤-arrestin-recruited ligase in the absence of GPCR activation. The ability of ␤-arrestins to play different scaffold functions would allow coordination of both Mdm2-dependent and -independent processes aimed at the specific modulation of GRK2 turnover in different signaling contexts.

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“…The concentration of GRK2 was elevated in neutrophils from patients with sepsis, as well as in control neutrophils treated with cytokines plus lipopolysaccharide (to mimic septic environment) that might result in septic neutrophils’ insensitivity to chemoattractants (Arraes et al, 2006). Neonatal experimental hypoxia/ischemia in rats decreased the expression of GRK2, but not GRK6, in the ipsilateral hippocampus that suffered severe damage following the injury (Lombardi et al, 2004). …”

Section: Physiological and Pathological Roles Of Grk Isoformsmentioning

confidence: 99%

G protein-coupled receptor kinases: More than just kinases and not only for GPCRs

Gurevich

Tesmer

Mushegian

et al. 2012

Pharmacology & Therapeutics

384

414

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G protein-coupled receptor (GPCR) kinases (GRKs) are best known for their role in homologous desensitization of GPCRs. GRKs phosphorylate activated receptors and promote high affinity binding of arrestins, which precludes G protein coupling. GRKs have a multidomain structure, with the kinase domain inserted into a loop of a regulator of G protein signaling homology domain. Unlike many other kinases, GRKs do not need to be phosphorylated in their activation loop to achieve an activated state. Instead, they are directly activated by docking with active GPCRs. In this manner they are able to selectively phosphorylate Ser/Thr residues on only the activated form of the receptor, unlike related kinases such as protein kinase A. GRKs also phosphorylate a variety of non-GPCR substrates and regulate several signaling pathways via direct interactions with other proteins in a phosphorylation-independent manner. Multiple GRK subtypes are present in virtually every animal cell, with the highest expression levels found in neurons, with their extensive and complex signal regulation. Insufficient or excessive GRK activity was implicated in a variety of human disorders, ranging from heart failure to depression to Parkinson’s disease. As key regulators of GPCR-dependent and -independent signaling pathways, GRKs are emerging drug targets and promising molecular tools for therapy. Targeted modulation of expression and/or of activity of several GRK isoforms for therapeutic purposes was recently validated in cardiac disorders and Parkinson’s disease.

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Hypoxia/Ischemia Modulates G Protein–Coupled Receptor Kinase 2 and β-Arrestin-1 Levels in the Neonatal Rat Brain

Cited by 44 publications

References 34 publications

Low Endogenous G-Protein-Coupled Receptor Kinase 2 Sensitizes the Immature Brain to Hypoxia–Ischemia-Induced Gray and White Matter Damage

Low Endogenous G-Protein-Coupled Receptor Kinase 2 Sensitizes the Immature Brain to Hypoxia–Ischemia-Induced Gray and White Matter Damage

Multiple Scaffolding Functions of β-Arrestins in the Degradation of G Protein-coupled Receptor Kinase 2

G protein-coupled receptor kinases: More than just kinases and not only for GPCRs

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