Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating

Carlson, Gerald M.; Lin, Robert; Chen, Y.; Brookshire, Bethany R.; White, Rachel; Lucki, Irwin; Siegel, Steven J.; Kim, S.F.

doi:10.1016/j.neuroscience.2016.02.063

Cited by 20 publications

(19 citation statements)

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“…Moreover, a study showed that the deletion of Dexras1 reduced NMDA-induced iron uptake and NMDA toxicity in cortical neurons and retinal ganglion cells (Chen et al, 2013). Moreover, Dexras1-KO mice showed increased expression of the NR2A subunit of the NMDAR (Carlson et al, 2016), a subunit that is preferentially located at synapses and related to NMDAR pro-survival signaling; this strongly suggests the existence of a functional crosstalk between the NMDA-induced iron intracellular signaling and the physiological NMDAR function. Interestingly, intracellular iron released from lysosomes has been shown to modulate NMDAR synaptic excitability via Dexras1 (White et al, 2016), and iron is needed post-synaptically to activate Ca 2+ -dependent pathways downstream NMDAR (Muñoz et al, 2011).…”

Section: The Ferroptotic Component Of Stroke-induced Neurodegenerationmentioning

confidence: 99%

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

DeGregorio-Rocasolano

2019

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In general, iron represents a double-edged sword in metabolism in most tissues, especially in the brain. Although the high metabolic demands of brain cells require iron as a redox-active metal for ATP-producing enzymes, the brain is highly vulnerable to the devastating consequences of excessive iron-induced oxidative stress and, as recently found, to ferroptosis as well. The blood–brain barrier (BBB) protects the brain from fluctuations in systemic iron. Under pathological conditions, especially in acute brain pathologies such as stroke, the BBB is disrupted, and iron pools from the blood gain sudden access to the brain parenchyma, which is crucial in mediating stroke-induced neurodegeneration. Each brain cell type reacts with changes in their expression of proteins involved in iron uptake, efflux, storage, and mobilization to preserve its internal iron homeostasis, with specific organelles such as mitochondria showing specialized responses. However, during ischemia, neurons are challenged with excess extracellular glutamate in the presence of high levels of extracellular iron; this causes glutamate receptor overactivation that boosts neuronal iron uptake and a subsequent overproduction of membrane peroxides. This glutamate-driven neuronal death can be attenuated by iron-chelating compounds or free radical scavenger molecules. Moreover, vascular wall rupture in hemorrhagic stroke results in the accumulation and lysis of iron-rich red blood cells at the brain parenchyma and the subsequent presence of hemoglobin and heme iron at the extracellular milieu, thereby contributing to iron-induced lipid peroxidation and cell death. This review summarizes recent progresses made in understanding the ferroptosis component underlying both ischemic and hemorrhagic stroke subtypes.

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Section: The Ferroptotic Component Of Stroke-induced Neurodegenerationmentioning

confidence: 99%

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

DeGregorio-Rocasolano

2019

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“…Finally, we examined the potential effects of dexras1 ablation on NMDA receptor-mediated glutamatergic signaling in the DG under sedentary and exercise conditions. Several studies have uncovered functional interactions between Dexras1 and NMDA receptor signaling 45 – 48 . Moreover, glutamatergic signaling can, either directly or indirectly (through the regulation of paracrine signals), affect cell proliferation and survival in the hippocampus 18 .…”

Section: Resultsmentioning

confidence: 99%

“…Due to their extremely low numbers and rapid clearance, apoptotic cells are difficult to quantify in the DG: thus, discrimination between these two possibilities requires an alternate approach beyond the conventional methods of using in situ apoptotic markers. Also, it should be noted that dexras1 ablation affects hippocampal-dependent memory and learning under basal conditions 48 . It would be interesting to know whether the alterations in exercise-dependent hippocampal neurogenesis in dexras1 −/− mice impact the cognitive-enhancing effects of exercise.…”

Section: Discussionmentioning

confidence: 99%

Dexras1 is a homeostatic regulator of exercise-dependent proliferation and cell survival in the hippocampal neurogenic niche

Bouchard-Cannon

Lowden

Trinh

et al. 2018

Sci Rep

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Adult hippocampal neurogenesis is highly responsive to exercise, which promotes the proliferation of neural progenitor cells and the integration of newborn granule neurons in the dentate gyrus. Here we show that genetic ablation of the small GTPase, Dexras1, suppresses exercise-induced proliferation of neural progenitors, alters survival of mitotic and post-mitotic cells in a stage-specific manner, and increases the number of mature newborn granule neurons. Dexras1 is required for exercise-triggered recruitment of quiescent neural progenitors into the cell cycle. Pharmacological inhibition of NMDA receptors enhances SGZ cell proliferation in wild-type but not dexras1-deficient mice, suggesting that NMDA receptor-mediated signaling is dependent on Dexras1. At the molecular level, the absence of Dexras1 abolishes exercise-dependent activation of ERK/MAPK and CREB, and inhibits the upregulation of NMDA receptor subunit NR2A, bdnf, trkB and vegf-a expression in the dentate gyrus. Our study reveals Dexras1 as an important stage-specific regulator of exercise-induced neurogenesis in the adult hippocampus by enhancing pro-mitogenic signaling to neural progenitor cells and modulating cell survival.

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“…S-nitrosylated DEXRAS1/RASD1 may also bind to the divalent metal transporter 1 (DMT1) via the scaffold protein, peripheral benzodiazepine receptor-associated protein 7 (PAP7), and enhance NMDAR-induced extracellular iron uptake (Cheah et al 2006). More recently, DEXRAS1/RASD1 has been shown to mediate NMDAR-triggered release of lysosomal stores of iron (White et al 2016). Cytosolic iron suppresses subsequent NMDAR activity by inhibiting a RASD1, Fig.…”

Section: Molecular and Cell Signalingmentioning

confidence: 99%

Rap Guanine Nucleotide Exchange Factor 3 (Rapgef3)

2018

Encyclopedia of Signaling Molecules

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Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating

Cited by 20 publications

References 58 publications

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

Dexras1 is a homeostatic regulator of exercise-dependent proliferation and cell survival in the hippocampal neurogenic niche

Rap Guanine Nucleotide Exchange Factor 3 (Rapgef3)

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