S-nitrosylation of GAD65 is implicated in decreased GAD activity and oxygen-induced seizures.
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2017-07
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Breathing oxygen at partial pressures ≥2.5 atmospheres absolute, which can occur in diving and hyperbaric oxygen (HBO2) therapy, can rapidly become toxic to the central nervous system (CNS). This neurotoxicity culminates in generalized EEG epileptiform discharges, tonic-clonic convulsions and ultimately death. Increased production of neuronal nitric oxide (NO) has been implicated in eliciting hyperoxic seizures by altering the equilibrium between glutamatergic and GABAergic synaptic transmission. Inhibition of glutamic acid decarboxylase (GAD) activity in HBO2 promotes this imbalance; however, the mechanisms by which this occurs is unknown. Therefore, we conducted a series of experiments using mice, a species that is highly susceptible to CNS oxygen toxicity, to explore the possibility that NO modulates GABA metabolism. Mice were exposed to 100% oxygen at 4 ATA for various durations, and brain GAD and GABA transaminase (GABA-T) activity, as well as S-nitrosylation of GAD65 and GAD67 were determined. HBO2 inhibited GAD activity by 50% and this was negatively correlated with S-nitrosylation of GAD65, whereas GABA-T activity and S-nitrosylation of GAD67 were unaltered. These results suggest a new mechanism by which NO alters GABA metabolism, leading to neuroexcitation and seizures in HBO2.
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Gasier, Heath G, Ivan T Demchenko, Lynn G Tatro and Claude A Piantadosi (2017). S-nitrosylation of GAD65 is implicated in decreased GAD activity and oxygen-induced seizures. Neuroscience letters, 653. pp. 283–287. 10.1016/j.neulet.2017.05.067 Retrieved from https://hdl.handle.net/10161/24104.
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Scholars@Duke
Heath Gasier
Dr. Gasier is a physiologist and nutritionist. His research is focused on understanding how breathing altered PO2 impacts cell physiology in the lung, brain, and skeletal muscle. Emphasis is placed on mitochondrial quality control (dynamics, mitophagy, and biogenesis) and bioenergetics. He uses in vivo and in vitro models, and employs an array of methods (e.g., confocal and electron microscopy, Seahorse respiration, immunoblotting, RT-qPCR, ELISA’s, isotope tracers, and 10X genomics) for hypothesis testing. The goal of his research is to improve the operational capacity of divers and safety of hyperoxia in hyperbaric and critical care medicine. Dr. Gasier believes in a hands-on mentoring approach and individualized training plans based on mentee’s aspirations. He is committed to lifetime learning and contributing to knowledge advancement.
Claude Anthony Piantadosi
Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of acute organ failure, particularly acute lung injury (ALI), with an emphasis on the molecular regulatory roles of the physiological gases— oxygen, carbon monoxide, and nitric oxide— as they relate to the damage responses to acute inflammation. The basic science focuses on oxidative processes and redox-regulation, especially the molecular mechanisms by which reactive oxygen and nitrogen species transmit biological signals involved in the maintenance of energy metabolism and mitochondrial health, but also contribute to pathogenesis and to the resolution of tissue injury.
Clinically, ALI and the related syndrome of multiple organ failure has a high mortality, which is related to the host inflammatory response, but is not well understood scientifically; thus, the laboratory is devoted to understanding these mechanisms in the context of the host response to relevant but well-controlled experimental manipulations including hyperoxia, bacterial infections, toxic drugs, and cytokine/chemokine signals. The approach relies on animal models, mainly transgenic and knockout mice, and cell models, especially lung and heart cells to evaluate and understand the physiology, pathology, and cell and molecular biology of the injury responses, to test independent and integrated mechanisms, and to devise interventions to prevent damage.
Apart from the lung, significant work is devoted to understanding damage to the heart, brain, liver, and kidney caused by these immune mechanisms, specifically emphasizing the role of mitochondria, key targets and sources of oxidative damage. This damage compromises their ability to support energy homeostasis and advanced cellular functions, and impacts on the important roles these organelles play in cell death by apoptosis and necrosis as well as in the resolution of cellular damage and inflammation.
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