PKA‐mediated phosphorylation of Dexras1 suppresses iron trafficking by inhibiting S‐nitrosylation

Chen, Yong; Mathias, Lauren; Falero-Perez, Juliana; Kim, Sangwon F.

doi:10.1016/j.febslet.2015.08.041

Cited by 15 publications

(13 citation statements)

References 58 publications

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“…In the present study, we provided direct evidence that ketamine or sevoflurane exposure caused an upregulation of NMDAR subunits, which might be a compensatory upregulation of NMDAR subunits [34][35][36]. Accompanying with that, both ketamine and sevoflurane induced upregulation of RASD1, which could form a ternary complex with PAP7 and DMT1 and thus enhance the ability of NMDAR to activate DMT1 for iron uptake [8,37]. The activation was inhibited by administration of DMT1 inhibitor DMT1i in this study to prevent iron accumulation in neurons, which attenuated iron-induced neurotoxicity.…”

Section: Discussionsupporting

confidence: 65%

“…Previous experiments revealed that ketamine or sevoflurane treatment upregulates the expression of NMDAR subunits (compensatory regulation as a consequence of continued or prolonged NMDAR blockade) [34][35][36]. Moreover, NMDAR upregulation leads to the activation of RASD1 (also called as Dex-ras1), a novel GTPase, which interacts with iron importer DMT1 and enhances DMT1-mediated iron uptake and iron releasing from lysosome [8,37]. Here, we found increased expression of NMDAR1 (NR1) and NMDAR2A (NR2A), as well as RASD1 and DMT1, after 6 h ketamine or sevoflurane treatment (Fig.…”

Section: Nmdar-mediated Iron Transport Pathway Is Involved In Ga-indumentioning

confidence: 99%

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Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits

Yang

Cao

et al. 2020

J Neuroinflammation

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Background: Increasing evidence suggests that multiple or long-time exposure to general anaesthesia (GA) could be detrimental to cognitive development in young subjects and might also contribute to accelerated neurodegeneration in the elderly. Iron is essential for normal neuronal function, and excess iron in the brain is implicated in several neurodegenerative diseases. However, the role of iron in GA-induced neurotoxicity and cognitive deficits remains elusive. Methods: We used the primary hippocampal neurons and rodents including young rats and aged mice to examine whether GA impacted iron metabolism and whether the impact contributed to neuronal outcomes. In addition, a pharmacological suppression of iron metabolism was performed to explore the molecular mechanism underlying GA-mediated iron overload in the brain. Results: Our results demonstrated that GA, induced by intravenous ketamine or inhalational sevoflurane, disturbed iron homeostasis and caused iron overload in both in vitro hippocampal neuron culture and in vivo hippocampus. Interestingly, ketamine-or sevoflurane-induced cognitive deficits, very likely, resulted from a novel iron-dependent regulated cell death, ferroptosis. Notably, iron chelator deferiprone attenuated the GA-induced mitochondrial dysfunction, ferroptosis, and further cognitive deficits. Moreover, we found that GA-induced iron overload was activated by NMDAR-RASD1 signalling via DMT1 action in the brain. Conclusion: We conclude that disturbed iron metabolism may be involved in the pathogenesis of GA-induced neurotoxicity and cognitive deficits. Our study provides new vision for consideration in GA-associated neurological disorders.

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Section: Discussionsupporting

confidence: 65%

Section: Nmdar-mediated Iron Transport Pathway Is Involved In Ga-indumentioning

confidence: 99%

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits

Yang

Cao

et al. 2020

J Neuroinflammation

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“…NMDAR is one of the two main targets to the GAs. Previous experiments revealed that ketamine or sevoflurane induced a compensatory upregulation of NMDAR expression [32,33], which promoted iron uptake through DMT1 action [8,34]. Here we found increased expression of NMDAR1 (NR1) and NMDAR2A (NR2A), as well as RASD1 and DMT1, after 6 h ketamine or sevoflurane treatment (Fig.…”

Section: Nmdar-rasd1-dmt1 Pathway Is Involved In Ga-induced Iron Oversupporting

confidence: 66%

“…Accompanying with that, both ketamine and sevoflurane induced upregulation of NR1, NR2A, and RASD1. RASD1 (also called dexRas), a novel GTPase that acts at a confluence of signalling mechanisms associated with psychiatric and neurological disease, mediates iron trafficking and NMDA-dependent neurodegeneration by forming a ternary complex with DMT1, thus enhances the ability of NMDAR to activate DMT1 [8,34], . The activation was inhibited by administration of DMT1 inhibitor in this study to prevent iron accumulation in neurons.…”

Section: Discussionmentioning

confidence: 99%

Iron Overload contributes to General Anesthesia-induced Neurotoxicity and Cognitive Deficits

Yang

Cao

et al. 2019

Preprint

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Background Increasing evidence suggests that exposure to general anesthesia (GA) could be detrimental to cognitive development in young subjects, and might also contribute to accelerated neurodegeneration in the elderly. Iron is essential for normal neuronal function and excess iron in brain is a hallmark of neuroinflammation and is implicated in several neurodegenerative diseases. However, the role of iron in GA-induced neurotoxicity and cognitive deficits has not been studied.Methods We used the primary hippocampal neurons and rodents including young rats and aged mice to examine whether GA impacts iron metabolism and whether the impact contributed to neuronal outcomes. In addition, a pharmacological suppression of iron metabolism was performed to explore the molecular mechanism underlying GAs-mediated iron overload in the brain.Results Our results demonstrated that GA, induced by intravenous ketamine or inhalational sevoflurane, disturbed iron homeostasis and caused iron overload in both in vitro hippocampal neuron culture and in vivo hippocampus. Interestingly, ketamine or sevoflurane-induced cognitive deficits, very likely, result from a novel regulated iron-dependent cell death, ferroptosis. Notably, iron chelator deferiprone attenuated the GA-induced mitochondrial dysfunctions, ferroptosis, and further cognitive deficits. Moreover, we found that GA-induced iron overload was activated by NMDAR-RASD1 signalling via DMT1 action in the brain.Conclusion We conclude that disturbed iron metabolism may be involved in the pathogenesis of GA-induced neurotoxicity and cognitive deficits. Our study provides new insights into a potential novel therapy for prevention in GA-associated neurological disorders.

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“…The phosphorylation of RhoA on Ser‐188 by cAMP‐dependent PKA, inducing its inhibition and consequently RhoA/Rho‐kinase activity inhibition, leads to the normalisation of P‐MYPT‐1 levels . Furthermore, it was reported that PKA activation may inhibit protein S‐nitrosylation . This complementary effect may also contribute to the beneficial impact of colforsin.…”

Section: Discussionmentioning

confidence: 99%

cAMP‐dependent regulation of RhoA/Rho‐kinase attenuates detrusor overactivity in a novel mouse experimental model

Akakpo¹,

Musicki²,

Burnett³

2017

BJU International

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Objectives To investigate detrusor function and cAMP activation as a possible target for detrusor overactivity in an experimental model lacking a key denitrosylation enzyme, S-nitrosoglutathione reductase (GSNOR). Materials and Methods GSNOR-deficient (GSNOR−/−) (n=30) and wild-type (WT) mice (n=26) were treated for 7 days with the cAMP activator, colforsin (1mg/kg), or vehicle intraperitoneally. Cystometric studies or molecular analyses of bladder specimens were performed. Bladder function indices and expression levels of proteins that regulate detrusor relaxation (nitric oxide synthase pathway) or contraction (RhoA/Rho-kinase pathway) and oxidative stress were assessed. Student t-test and one-way ANOVA were used. Results GSNOR−/− mice showed a significant increase (P<0.05) in voiding and non-voiding contraction frequencies compared to WT mice (Cohen’s effect size values d = 1.82 and 2.52, respectively). Colforsin normalized these abnormalities (Cohen’s effect size values d = 1.85 and 1.28, respectively). Western blot analyses showed an up-regulation of the RhoA/Rho-kinase pathway reflected by a significant increase (P<0.05) of phosphorylated-MYPT1 expression in GSNOR−/− mouse bladders, which was reversed by colforsin treatment. An increased level (P<0.05) of gp91phox expression in bladders of GSNOR−/− mice was observed without significant change after colforsin treatment. Neuronal and endothelial nitric oxide synthase phosphorylation on Ser-1412 and Ser-1177, respectively, did not differ between GSNOR−/− and WT mouse bladders irrespective of colforsin treatment. Conclusion Impaired denitrosylation is associated with detrusor overactivity that is linked with upregulated RhoA/Rho-kinase signaling. Colforsin reverses physiologic and molecular abnormalities. This study describes a novel model of detrusor overactivity and suggests a possible basis for its treatment.

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PKA‐mediated phosphorylation of Dexras1 suppresses iron trafficking by inhibiting S‐nitrosylation

Cited by 15 publications

References 58 publications

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits

Iron Overload contributes to General Anesthesia-induced Neurotoxicity and Cognitive Deficits

cAMP‐dependent regulation of RhoA/Rho‐kinase attenuates detrusor overactivity in a novel mouse experimental model

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