Glycogen synthase kinase-3 is essential for β-arrestin-2 complex formation and lithium-sensitive behaviors in mice

O’Brien, William T.; Huang, Jian; Buccafusca, Roberto; Garskof, Julie; Valvezan, Alexander J.; Berry, Gerard T.; Klein, Peter S.

doi:10.1172/jci45194

Cited by 101 publications

(97 citation statements)

References 61 publications

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“…In nerves from Gnpat-KO mice, we observed increased levels of Tyr216 phosphorylation and decreased levels of Ser9 phosphorylation, which, combined, indicate overtly active GSK3β (41). Lithium, a known inhibitor of GSK3β, can directly inhibit the kinase through Mg 2+ competition and can indirectly inhibit GSK3β by promoting further inhibition through Ser9 phosphorylation (42,43). Lithium administration to Gnpat-KO mice was able to normalize GSK3β phosphorylation status, induced the stimulation of Schwann cell differentiation, rescued the radial sorting defect, and improved myelination independently of the plasmalogen defect.…”

Section: Methodsmentioning

confidence: 81%

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

Silva¹,

Eira²,

Lopes³

et al. 2014

J. Clin. Invest.

111

117

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Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3β (GSK3β) in nerves of mutant mice. Treatment with GSK3β inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.

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Section: Methodsmentioning

confidence: 81%

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

Silva¹,

Eira²,

Lopes³

et al. 2014

J. Clin. Invest.

111

117

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“…Other work (40) has previously demonstrated such complex in association with ␤-arrestin 2, a known partner of PAR 2 signaling. We decided to use the CMT93 cell line that we built deficient immunolabeling (yellow) of serine-9-phosphorylated GSK3␤ (inhibited form) in PAR2-deficient colonospheres and tumor spheroids compared with controls.…”

Section: A ␤-Arrestin2/pp2a/gsk3␤ Complex Supports the Cross Talk Betmentioning

confidence: 85%

PAR₂-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells

Nasri

Bonnet

Zwarycz

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Protease-activated receptors PAR1 and PAR2 play an important role in the control of epithelial cell proliferation and migration. However, the survival of normal and tumor intestinal stem/progenitor cells promoted by proinflammatory mediators may be critical in oncogenesis. The glycogen synthase kinase-3β (GSK3β) pathway is overactivated in colon cancer cells and promotes their survival and drug resistance. We thus aimed to determine PAR1 and PAR2 effects on normal and tumor intestinal stem/progenitor cells and whether they involved GSK3β. First, PAR1 and PAR2 were identified in colon stem/progenitor cells by immunofluorescence. In three-dimensional cultures of murine crypt units or single tumor Caco-2 cells, PAR2 activation decreased numbers and size of normal or cancerous spheroids, and PAR2-deficient spheroids showed increased proliferation, indicating that PAR2 represses proliferation. PAR2-stimulated normal cells were more resistant to stress (serum starvation or spheroid passaging), suggesting prosurvival effects of PAR2. Accordingly, active caspase-3 was strongly increased in PAR2-deficient normal spheroids. PAR2 but not PAR1 triggered GSK3β activation through serine-9 dephosphorylation in normal and tumor cells. The PAR2-triggered GSK3β activation implicates an arrestin/PP2A/GSK3β complex that is dependent on the Rho kinase activity. Loss of PAR2 was associated with high levels of GSK3β nonactive form, strengthening the role of PAR2 in GSK3β activation. GSK3 pharmacological inhibition impaired the survival of PAR2-stimulated spheroids and serum-starved cells. Altogether our data identify PAR2/GSK3β as a novel pathway that plays a critical role in the regulation of stem/progenitor cell survival and proliferation in normal colon crypts and colon cancer.

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“…AKT, βarr2, and PP2A form a signaling complex in a DA-dependent fashion, and GSK3β and D2Rs are required to form this complex (5,6,23). We performed coimmunoprecipitations (Co-IPs) (SI Materials and Methods) to analyze the interaction between AKT, βarr2, and PP2A in D2GSK3β −/− and D1GSK3β −/− mice and their respective controls.…”

Section: Resultsmentioning

confidence: 99%

“…Lithium has been used in the clinic for many years as a mood stabilizer but the mechanisms that mediate its effects are still debated. However, several other mechanisms to account for the action of lithium have been proposed including inositol depletion, indirect activation of AKT, and inhibition of a β-arrestin/ AKT signaling complex (15,23,(48)(49)(50). Behavioral tests such as locomotion, tail-suspension test (TST), forced swim test (FST), and dark-light emergence test in mice are sensitive to lithium treatment (51,52).…”

Section: Discussionmentioning

confidence: 99%

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Urs¹,

Snyder²,

Jacobsen³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Several studies in rodent models have shown that glycogen synthase kinase 3 β (GSK3β) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3β through a β-arrestin2/protein kinase B (PKB or Akt)/protein phosphatase 2A (PP2A) signaling complex regulates dopamine (DA)-and lithium-sensitive behaviors and is required to mediate endophenotypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antagonize DA D2 receptor (D2R)/β-arrestin2 interactions more efficaciously than G-protein-dependent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3β in regulating DA-or lithium-sensitive behaviors, we generated conditional knockouts of GSK3β, where GSK3β was deleted in either DA D1-or D2-receptor-expressing neurons. We analyzed these mice for behaviors commonly used to test antipsychotic efficacy or behaviors that are sensitive to lithium treatment. Mice with deletion of GSK3β in D2 (D2GSK3β −/− ) but not D1 (D1GSK3β −/− ) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3β −/− or D1GSK3β −/− mice compared with control mice. Interestingly, genetic stabilization of β-catenin, a downstream target of GSK3β, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3β −/− or D1GSK3β −/− mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be β-arrestin2-and GSK3β-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3β but not stabilization of β-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.functional selectivity | schizophrenia | bipolar disorder | striatum | frontal cortex

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Glycogen synthase kinase-3 is essential for β-arrestin-2 complex formation and lithium-sensitive behaviors in mice

Cited by 101 publications

References 61 publications

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

PAR₂-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

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Glycogen synthase kinase-3 is essential for β-arrestin-2 complex formation and lithium-sensitive behaviors in mice

Cited by 101 publications

References 61 publications

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

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PAR₂-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells