Na+–K+-ATPase inhibition and depolarization induce glutamate release via reverse Na+-dependent transport in spinal cord white matter

Li, S; Stys, Peter K.

doi:10.1016/s0306-4522(01)00385-2

Cited by 90 publications

(46 citation statements)

References 59 publications

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“…Glutamate is transported in a sodium-and potassium-dependent fashion utilizing the sodium and potassium gradients set by Na,K-ATPase. It has been shown that inhibition of Na,K-ATPase by ouabain will reduce the amplitude of neuronal compound action potentials (41), and this diminished neuronal activity was shown to be a result of toxicity mediated in part by glutamate release through reverse sodium-dependent glutamate transport. Interestingly, a recent report by Rozzo et al (43) demonstrated that the spontaneous rhythmicity of network spinal cord neurons is disrupted with Na,K-ATPase inhibition by strophanthidin, a cardiotonic steroid related to ouabain (43).…”

Section: Discussionmentioning

confidence: 99%

The Na,K-ATPase α2 Isoform Is Expressed in Neurons, and Its Absence Disrupts Neuronal Activity in Newborn Mice

Moseley¹,

Lieske²,

Wetzel³

et al. 2003

Journal of Biological Chemistry

145

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Na,K-ATPase is an ion transporter that impacts neural and glial physiology by direct electrogenic activity and the modulation of ion gradients. Its three isoforms in brain have cell-type and development-specific expression patterns. Interestingly, our studies demonstrate that in late gestation, the ␣2 isoform is widely expressed in neurons, unlike in the adult brain, in which ␣2 has been shown to be expressed primarily in astrocytes. This unexpected distribution of ␣2 isoform expression in neurons is interesting in light of our examination of mice lacking the ␣2 isoform which fail to survive after birth. These animals showed no movement; however, defects in gross brain development, muscle contractility, neuromuscular transmission, and lung development were ruled out. Akinesia suggests a primary neuronal defect and electrophysiological recordings in the pre-Bö tzinger complex, the brainstem breathing center, showed reduction of respiratory rhythm activity, with less regular and smaller population bursts. These data demonstrate that the Na,K-ATPase ␣2 isoform could be important in the modulation of neuronal activity in the neonate.

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Section: Discussionmentioning

confidence: 99%

The Na,K-ATPase α2 Isoform Is Expressed in Neurons, and Its Absence Disrupts Neuronal Activity in Newborn Mice

Moseley¹,

Lieske²,

Wetzel³

et al. 2003

Journal of Biological Chemistry

145

View full text Add to dashboard Cite

show abstract

“…Ouabain has been shown to impair glutamate transporter activity, and injection of ouabain into neonatal rat brain induces excitotoxicity secondary to cellular membrane depolarization (Li and Stys, 2001;Veldhuis et al, 2003). In the CNS, it has been estimated that at least 40% of the energy delivered by respiration is required by Na,K-ATPase to maintain ion gradients across cell membranes (Astrup et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

Glutamate Transporter Coupling to Na,K-ATPase

Rose

Koo²,

Antflick³

et al. 2009

Journal of Neuroscience

277

229

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Deactivation of glutamatergic signaling in the brain is mediated by glutamate uptake into glia and neurons by glutamate transporters. Glutamate transporters are sodium-dependent proteins that putatively rely indirectly on Na,K-ATPases to generate ion gradients that drive transmitter uptake. Based on anatomical colocalization, mutual sodium dependency, and the inhibitory effects of the Na,K-ATPase inhibitor ouabain on glutamate transporter activity, we postulated that glutamate transporters are directly coupled to Na,K-ATPase and that Na,K-ATPase is an essential modulator of glutamate uptake. Na,K-ATPase was purified from rat cerebellum by tandem anion exchange and ouabain affinity chromatography, and the cohort of associated proteins was characterized by mass spectrometry. The ␣1-␣3 subunits of Na,K-ATPase were detected, as were the glutamate transporters GLAST and GLT-1, demonstrating that glutamate transporters copurify with Na,K-ATPases. The link between glutamate transporters and Na,K-ATPase was further established by coimmunoprecipitation and colocalization. Analysis of the regulation of glutamate transporter and Na,K-ATPase activities was assessed using

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“…Thus, cellular respiration falls off as mitochondrial dysfunction occurs (Sullivan et al, 2007) and local ATP concentrations decrease (Anderson et al, 1980), compromising the cell's energy supply (Sullivan et al, 2007) and hampering the ability of ionic pumping mechanisms, such as the Na-K-ATPase transporter (Faden et al, 1987;Li and Stys, 2001), to restore ionic homeostasis. Free radical factors, including nitric oxide (NO) (Merrill et al, 1993;Hamada et al, 1996) and reactive oxygen species (ROS) (Hall and Braughler, 1993), accumulate, damaging DNA.…”

mentioning

confidence: 99%

Pathology Dynamics Predict Spinal Cord Injury Therapeutic Success

Mitchell

Lee

2008

Journal of Neurotrauma

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Secondary injury, the complex cascade of cellular events following spinal cord injury (SCI), is a major source of post-insult neuron death. Experimental work has focused on the details of individual factors or mechanisms that contribute to secondary injury, but little is known about the interactions among factors leading to the overall pathology dynamics that underlie its propagation. Prior hypotheses suggest that the pathology is dominated by interactions, with therapeutic success lying in combinations of neuroprotective treatments. In this study, we provide the first comprehensive, system-level characterization of the entire secondary injury process using a novel relational model methodology that aggregates the findings of *250 experimental studies. Our quantitative examination of the overall pathology dynamics suggests that, while the pathology is initially dominated by ''fire-like,'' rate-dependent interactions, it quickly switches to a ''flood-like,'' accumulation-dependent process with contributing factors being largely independent. Our evaluation of *20,000 potential single and combinatorial treatments indicates this flood-like pathology results in few highly influential factors at clinically realistic treatment time frames, with multi-factor treatments being merely additive rather than synergistic in reducing neuron death. Our findings give new fundamental insight into the understanding of the secondary injury pathology as a whole, provide direction for alternative therapeutic strategies, and suggest that ultimate success in treating SCI lies in the pursuit of pathology dynamics in addition to individually involved factors.

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Na+–K+-ATPase inhibition and depolarization induce glutamate release via reverse Na+-dependent transport in spinal cord white matter

Cited by 90 publications

References 59 publications

The Na,K-ATPase α2 Isoform Is Expressed in Neurons, and Its Absence Disrupts Neuronal Activity in Newborn Mice

The Na,K-ATPase α2 Isoform Is Expressed in Neurons, and Its Absence Disrupts Neuronal Activity in Newborn Mice

Glutamate Transporter Coupling to Na,K-ATPase

Pathology Dynamics Predict Spinal Cord Injury Therapeutic Success

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