Nitric Oxide Modulates Sodium Vitamin C Transporter 2 (SVCT-2) Protein Expression via Protein Kinase G (PKG) and Nuclear Factor-κB (NF-κB)

Portugal, Camila C.; Encarnação, Thaísa Godinho da; Socodato, Renato; Rodrigues-Moreira, Sarah; Brudzewsky, Dan; Ambrósio, António Francisco; Paes‐de‐Carvalho, Roberto

doi:10.1074/jbc.m111.260166

Cited by 46 publications

(45 citation statements)

References 61 publications

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“…Furthermore, in E8 cultures, L-arginine treatment has already been described to increase endogenous NO production in an nNOS-dependent manner. 14,22 Interestingly, L-arginine administration promoted robust dose-dependent neuronal death in E6 purified cultures (Figure 2c) but it increased the viability of cultured E8 neurons (Figure 2e). Similarly, inhibiting basal NOS activity with L-NAME increased the viability of E6 neurons ( Figure 2d) and promoted neuronal death in cultured E8 neurons (Figure 2f).…”

Section: Resultsmentioning

confidence: 98%

“…Considering the capacity of microenvironmental molecules to modulate/determine retinal neuronal cells development, and taking into account the neuromodulatory role played by NO in our culture system, 11,14,15,23 we tested whether prolonged NO treatment of cultured neurons would modulate the viability of those cells. S-nitroso-N-acetyl-D,L-penicillamine (SNAP; NO donor) effect was only detected when it was added 2 h after seeding E6 and E8 neurons, designed here as E6C0 or E8C0 (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…13 In such cultures, endogenous and exogenous NO 1 modulate NF-kB activation and ascorbate transport through the canonical NO pathway. 14 In addition, excitatory retinal cell death induced by a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is regulated by nNOS activation. 15 Therefore, NO regulates diverse signaling events in the retina.…”

mentioning

confidence: 99%

“…20 Pre-and postsynaptic actions of cGKs may involve a parallel activation of the small GTPase RhoA in the regulation of actin cytoskeleton, which contributes to synaptic strengthening in hippocampal neurons. 21 In the developing retina, cGKs have been associated with Src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (Src)-induced neuronal apoptosis, 15 ascorbate transport 14 and cGKII, specifically, regulates V-Akt murine thymoma viral oncogene (AKT)/PKB activation. 22 In addition, cyclic AMPresponsive element-binding protein (CREB) phosphorylation in retinal cells is dependent on a cGK-mediated extracellular regulated kinase (ERK) activation, which directly correlates glutamate and NO pathway to nuclear CREB activity in the retina.…”

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confidence: 99%

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The nitric oxide-cGKII system relays death and survival signals during embryonic retinal development via AKT-induced CREB1 activation

et al. 2014

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During early neurogenesis, retinal neuronal cells display a conserved differentiation program in vertebrates. Previous studies established that nitric oxide (NO) and cGMP accumulation regulate essential events in retinal physiology. Here we used pharmacological and genetic loss-of-function to investigate the effects of NO and its downstream signaling pathway in the survival of developing avian retinal neurons in vitro and in vivo. Six-day-old (E6) chick retinal cells displayed increased calcium influx and produced higher amounts of NO when compared with E8 cells. L-arginine (substrate for NO biosynthesis) and S-nitroso-N-acetyl-D,L-penicillamine (SNAP; a nitrosothiol NO donor) promoted extensive cell death in E6 retinas, whereas in E8 both substances decreased apoptosis. The effect of NO at both periods was mediated by soluble guanylyl cyclase (sGC) and cGMP-dependent kinase (cGK) activation. In addition, shRNA-mediated cGKII knockdown prevented NO-induced cell death (E6) and cell survival (E8). This, NO-induced cell death or cell survival was not correlated with an early inhibition of retinal cell proliferation. E6 cells also responded differentially from E8 neurons regarding cyclic AMP-responsive element-binding protein (CREB) activation in the retina in vivo. NO strongly decreased nuclear phospho-CREB staining in E6 but it robustly enhanced CREB phosphorylation in the nuclei of E8 neurons, an effect that was completely abrogated by cGKII shRNAs at both embryonic stages. The ability of NO in regulating CREB differentially during retinal development relied on the capacity of cGKII in decreasing (E6) or increasing (E8) nuclear AKT (V-Akt murine thymoma viral oncogene) activation. Accordingly, inhibiting AKT prevented both cGKII shRNA-mediated CREB upregulation in E6 and SNAP-induced CREB activation in E8. Furthermore, shRNAmediated in vivo cGKII or in vitro CREB1 knockdown confirmed that NO/cGKII dualistically regulated the downstream CREB1 pathway and caspase activation in the chick retina to modulate neuronal viability. These data demonstrate that NO-mediated cGKII signaling may function to control the viability of neuronal cells during early retinal development via AKT/CREB1 activity. Cell Death and Differentiation (2014) 21, 915-928; doi:10.1038/cdd.2014.11; published online 14 February 2014The retina is part of the central nervous system (CNS) because of its derivation from the anterior neural tube. Mature retinal tissue is arranged in a laminar structure composed of seven major classes of cells: ganglion, horizontal, amacrine, bipolar, cone and rod photoreceptors and the Mü ller glia. 1 Early retinal tissue is a pseudo-stratified epithelium in which mitotically active neuronal precursor cells are found. Another noteworthy characteristic of vertebrate retinogenesis is the well-established chronology of cell-type generation, with ganglion cells generally being the first cells to be born and the Mü ller glia and bipolar neurons usually the last. Nevertheless, the differentiation periods of different cell type...

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The nitric oxide-cGKII system relays death and survival signals during embryonic retinal development via AKT-induced CREB1 activation

et al. 2014

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“…Nitric oxide is an important molecule, which regulates the release of several neuromodulators in the chick retina, such as GABA, glutamate, glutamine, ascorbate and others [88][89][90].…”

Section: No and The Release Of Neuromodulators In The Retinamentioning

confidence: 99%

Studying Nitric Oxide in the Developing Retina: Neuromodulatory Functions and Signaling Mechanisms

Socodato

Portugal²,

Encarnação³

et al. 2013

TONOJ

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Abstract:The retina is a highly organized structure responsible for transducing light stimulation into electrical responses. Retinal organization is conserved in all vertebrate species and the generation of retinal cell types is chronologically determined and fairly documented from amphibians to humans. Furthermore, the chick retina is a well-established experimental paradigm for neurochemical and developmental studies regarding the nervous system. Among many signaling molecules regulating retinal physiology, nitric oxide (NO) is likely to play a prominent role within the retina. NO is a gaseous signaling transmitter, which regulates a plethora of physiological functions within an organism, including high-order signaling events both in the developing and mature nervous system. In this review we focus on different aspects of NO signaling in regulating retinal cell neurochemistry, focusing mainly on developing chick retina as a prevalent experimental model. Based on literature and data gathered from our group we conclude that NO is a major atypical neurotransmitter in the retina, regulating signaling events associated with the development of embryonic retinal neurons and glial cells.

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c‐Src function is necessary and sufficient for triggering microglial cell activation

Socodato

Portugal

Domith

et al. 2014

Glia

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Microglial cells are the resident macrophages of the central nervous system. Their function is essential for neuronal tissue homeostasis. After inflammatory stimuli, microglial cells become activated changing from a resting and highly ramified cell shape to an amoeboid-like morphology. These morphological changes are associated with the release of proinflammatory cytokines and glutamate, as well as with high phagocytic activity. The acquisition of such phenotype has been associated with activation of cytoplasmic tyrosine kinases, including those of the Src family (SFKs). In this study, using both in vivo and in vitro inflammation models coupled to FRET-based time-lapse microscopy, lentiviruses-mediated shRNA delivery and genetic gain-of-function experiments, we demonstrate that among SFKs c-Src function is necessary and sufficient for triggering microglia proinflammatory signature, glutamate release, microglia-induced neuronal loss, and phagocytosis. c-Src inhibition in retinal neuroinflammation experimental paradigms consisting of intravitreal injection of LPS or ischemia-reperfusion injury significantly reduced microglia activation changing their morphology to a more resting phenotype and prevented neuronal apoptosis. Our data demonstrate an essential role for c-Src in microglial cell activation.

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Nitric Oxide Modulates Sodium Vitamin C Transporter 2 (SVCT-2) Protein Expression via Protein Kinase G (PKG) and Nuclear Factor-κB (NF-κB)

Cited by 46 publications

References 61 publications

The nitric oxide-cGKII system relays death and survival signals during embryonic retinal development via AKT-induced CREB1 activation

The nitric oxide-cGKII system relays death and survival signals during embryonic retinal development via AKT-induced CREB1 activation

Studying Nitric Oxide in the Developing Retina: Neuromodulatory Functions and Signaling Mechanisms

c‐Src function is necessary and sufficient for triggering microglial cell activation

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