Negative regulation of Rho signaling by insulin: role of nitric oxide/cGMP signaling pathways

Background: Polymorphonuclear neutrophils (PMNs) play a crucial role in the innate immune system’s response to microbial pathogens through the release of reactive nitrogen species, including Nitric Oxide (NO). </P><P> Methods: In neutrophils, NO is produced by the inducible Nitric Oxide Synthase (iNOS), which is regulated by various signaling pathways and transcription factors. N-nitrosodimethylamine (NDMA), a potential human carcinogen, affects immune cells. NDMA plays a major part in the growing incidence of cancers. Thanks to the increasing knowledge on the toxicological role of NDMA, the environmental factors that condition the exposure to this compound, especially its precursors- nitrates arouse wide concern. Results: In this article, we present a detailed summary of the molecular mechanisms of NDMA’s effect on the iNOS-dependent NO production in human neutrophils. Conclusion: This research contributes to a more complete understanding of the mechanisms that explain the changes that occur during nonspecific cellular responses to NDMA toxicity.

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Nitric Oxide Potentiates cAMP-Gated Cation Current in Feeding Neurons of Pleurobranchaea californica Independent of cAMP and cGMP Signaling Pathways

Journal of Neurophysiology ◽

10.1152/jn.0815.2005 ◽

2006 ◽

Vol 95 (5) ◽

pp. 3219-3227 ◽

Cited By ~ 1

Author(s):

N. G. Hatcher

Keyword(s):

Nitric Oxide ◽

Signaling Pathways ◽

Pleurobranchaea Californica ◽

Cation Current ◽

Cgmp Signaling ◽

Camp And Cgmp

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Inhibition of germinal vesicle breakdown by antioxidants and the roles of signaling pathways related to nitric oxide and cGMP during meiotic resumption in oocytes of a marine worm

Reproduction ◽

10.1530/rep-11-0358 ◽

2012 ◽

Vol 143 (3) ◽

pp. 261-270 ◽

Cited By ~ 8

Author(s):

Stephen A Stricker

Keyword(s):

Nitric Oxide ◽

Signaling Pathways ◽

Soluble Guanylate Cyclase ◽

Germinal Vesicle ◽

Germinal Vesicle Breakdown ◽

Nos Inhibitors ◽

Cgmp Signaling ◽

Sgc Stimulators ◽

Potential Interactions ◽

Downstream Mediator

In mammalian oocytes, cAMP elevations prevent the resumption of meiotic maturation and thereby block nuclear disassembly (germinal vesicle breakdown (GVBD)), whereas nitric oxide (NO) and its downstream mediator cGMP can either inhibit or induce GVBD. Alternatively, some invertebrate oocytes use cAMP to stimulate, rather than inhibit, GVBD, and in such cases, the effects of NO/cGMP signaling on GVBD remain unknown. Moreover, potential interactions between NO/cGMP and AMP-activated kinase (AMPK) have not been assessed during GVBD. Thus, this study analyzed intraoocytic signaling pathways related to NO/cGMP in a marine nemertean worm that uses cAMP to induce GVBD. For such tests, follicle-free nemertean oocytes were stimulated to mature by seawater (SW) and cAMP elevators. Based on immunoblots and NO assays of maturing oocytes, SW triggered AMPK deactivation, NO synthase (NOS) phosphorylation, and an NO elevation. Accordingly, SW-induced GVBD was blocked by treatments involving the AMPK agonist AICAR, antioxidants, the NO scavenger carboxy-PTIO, NOS inhibitors, and cGMP antagonists that target the NO-stimulated enzyme, soluble guanylate cyclase (sGC). Conversely, SW solutions combining NO/cGMP antagonists with a cAMP elevator restored GVBD. Similarly, AICAR plus a cAMP-elevating drug reestablished GVBD while deactivating AMPK and phosphorylating NOS. Furthermore, sGC stimulators and 8-Br-cGMP triggered GVBD. Such novel results indicate that NO/cGMP signaling can upregulate SW-induced GVBD and that cAMP-elevating drugs restore GVBD by overriding the inhibition of various NO/cGMP downregulators, including AMPK. Moreover, considering the opposite effects of intraoocytic cAMP in nemerteans vs mammals, these data coincide with previous reports that NO/cGMP signaling blocks GVBD in rats.

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Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0609778104 ◽

2007 ◽

Vol 104 (18) ◽

pp. 7699-7704 ◽

Cited By ~ 160

Author(s):

Andreas Friebe ◽

Evanthia Mergia ◽

Oliver Dangel ◽

Alexander Lange ◽

Doris Koesling

Keyword(s):

Nitric Oxide ◽

Guanylyl Cyclase ◽

Muscle Tone ◽

Pronounced Increase ◽

Unique Role ◽

Intestinal Dysmotility ◽

Cgmp Signaling ◽

Knockout Model

The signaling molecule nitric oxide (NO), first described as endothelium-derived relaxing factor (EDRF), acts as physiological activator of NO-sensitive guanylyl cyclase (NO-GC) in the cardiovascular, gastrointestinal, and nervous systems. Besides NO-GC, other NO targets have been proposed; however, their particular contribution still remains unclear. Here, we generated mice deficient for the β1 subunit of NO-GC, which resulted in complete loss of the enzyme. GC-KO mice have a life span of 3–4 weeks but then die because of intestinal dysmotility; however, they can be rescued by feeding them a fiber-free diet. Apparently, NO-GC is absolutely vital for the maintenance of normal peristalsis of the gut. GC-KO mice show a pronounced increase in blood pressure, underlining the importance of NO in the regulation of smooth muscle tone in vivo. The lack of an NO effect on aortic relaxation and platelet aggregation confirms NO-GC as the only NO target regulating these two functions, excluding cGMP-independent mechanisms. Our knockout model completely disrupts the NO/cGMP signaling cascade and provides evidence for the unique role of NO-GC as NO receptor.

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Role of Nitric Oxide Signaling Pathways in Brain Injuries

Current Chemical Biology ◽

10.2174/187231310792062666 ◽

2010 ◽

Vol 4 (3) ◽

pp. 250-261

Author(s):

Maria Aurelia Zorrilla-Zubilete ◽

Damian Gustavo Maur ◽

Maria Laura Palumbo ◽

Ana Maria Genaro

Keyword(s):

Nitric Oxide ◽

Signaling Pathways ◽

Brain Injuries ◽

Nitric Oxide Signaling

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Getting to NO Alzheimer’s Disease: Neuroprotection versus Neurotoxicity Mediated by Nitric Oxide

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/3806157 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 54

Author(s):

Rachelle Balez ◽

Lezanne Ooi

Keyword(s):

Nitric Oxide ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signaling Pathways ◽

Neuronal Excitability ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Protective Role ◽

Ionic Mechanisms

Alzheimer’s disease (AD) is a neurodegenerative disorder involving the loss of neurons in the brain which leads to progressive memory loss and behavioral changes. To date, there are only limited medications for AD and no known cure. Nitric oxide (NO) has long been considered part of the neurotoxic insult caused by neuroinflammation in the Alzheimer’s brain. However, focusing on early developments, prior to the appearance of cognitive symptoms, is changing that perception. This has highlighted a compensatory, neuroprotective role for NO that protects synapses by increasing neuronal excitability. A potential mechanism for augmentation of excitability by NO is via modulation of voltage-gated potassium channel activity (Kv7 and Kv2). Identification of the ionic mechanisms and signaling pathways that mediate this protection is an important next step for the field. Harnessing the protective role of NO and related signaling pathways could provide a therapeutic avenue that prevents synapse loss early in disease.

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Nitric oxide and cGMP influence axonogenesis of antennal pioneer neurons

Development ◽

10.1242/dev.127.21.4541 ◽

2000 ◽

Vol 127 (21) ◽

pp. 4541-4549 ◽

Cited By ~ 1

Author(s):

C. Seidel ◽

G. Bicker

Keyword(s):

Nitric Oxide ◽

Culture Medium ◽

Schistocerca Gregaria ◽

Soluble Guanylyl Cyclase ◽

Cgmp Signaling ◽

Pioneer Neurons ◽

Abnormal Pattern ◽

Pathway Formation ◽

Direct Activator

The grasshopper embryo has been used as a convenient system with which to investigate mechanisms of axonal navigation and pathway formation at the level of individual nerve cells. Here, we focus on the developing antenna of the grasshopper embryo (Schistocerca gregaria) where two siblings of pioneer neurons establish the first two axonal pathways to the CNS. Using immunocytochemistry we detected nitric oxide (NO)-induced synthesis of cGMP in the pioneer neurons of the embryonic antenna. A potential source of NO are NADPH-diaphorase-stained epithelial cells close to the basal lamina. To investigate the role of the NO/cGMP signaling system during pathfinding, we examined the pattern of outgrowing pioneer neurons in embryo culture. Pharmacological inhibition of soluble guanylyl cyclase (sGC) and of NO synthase (NOS) resulted in an abnormal pattern of pathway formation in the antenna. Axonogenesis of both pairs of pioneers was inhibited when specific NOS or sGC inhibitors were added to the culture medium; the observed effects include the loss axon emergence as well as retardation of outgrowth, such that growth cones do not reach the CNS. The addition of membrane-permeant cGMP or a direct activator of the sGC enzyme to the culture medium completely rescued the phenotype resulting from the block of NO/cGMP signaling. These results indicate that NO/cGMP signaling is involved in axonal elongation of pioneer neurons in the antenna of the grasshopper.

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