Enhanced Glutamate Uptake into Synaptic Vesicles Fueled by Vesicle-generated ATP from Phosphoenolpyruvate and ADP

Takeda, Kouji; Ueda, Tetsufumi

doi:10.1007/s11064-012-0864-4

Cited by 3 publications

(2 citation statements)

References 42 publications

(29 reference statements)

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“…Another important mechanism by which glycolytic inhibition might block seizures is related to synaptic transmission. It has been proposed that cytosolic ATP produced by glycolysis is important for presynaptic glutamate loading into synaptic vesicles (Ikemoto et al 2003;Takeda and Ueda 2012). Thus glycolytic inhibition reduces ATP production in the presynaptic terminal, which may decrease glutamate release.…”

Section: Discussionmentioning

confidence: 99%

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

Shao

Stafstrom

2017

Journal of Neurophysiology

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Neuronal activity is energy demanding and coupled to cellular metabolism. In this study, we investigated the effects of glycolytic inhibition with 2-deoxy-d-glucose (2-DG) on basal membrane properties, spontaneous neuronal firing, and epileptiform network bursts in hippocampal slices. The effect of glycolytic inhibition on basal membrane properties was examined in hippocampal CA1 neurons, which are not ordinarily active spontaneously. Intracellular application of 2-DG did not significantly alter the membrane input resistance, action-potential threshold, firing pattern, or input-output relationship of these neurons compared with simultaneously recorded neighboring neurons without intracellular 2-DG. The effect of glycolytic inhibition on neuronal firing was tested in spontaneously active hippocampal neurons (CA3) when synaptic transmission was left intact or blocked with AMPA, NMDA, and GABA receptor antagonists (DNQX, APV, and bicuculline, respectively). Under both conditions (synaptic activity intact or blocked), bath application of 2-DG (2 mM) blocked spontaneous firing in ~2/3 (67 and 71%, respectively) of CA3 pyramidal neurons. In contrast, neuronal firing of CA3 neurons persisted when 2-DG was applied intracellularly, suggesting that glycolytic inhibition of individual neurons is not sufficient to stop neuronal firing. The effects of 2-DG on epileptiform network bursts in area CA3 were tested in Mg-free medium containing 50 µM 4-aminopyridine. Bath application of 2-DG abolished these epileptiform bursts in a dose-dependent and all-or-none manner. Taken together, these data suggest that altered glucose metabolism profoundly affects cellular and network hyperexcitability and that glycolytic inhibition by 2-DG can effectively abrogate epileptiform activity. Neuronal activity is highly energy demanding and coupled to cellular metabolism. In this study, we demonstrate that glycolytic inhibition with 2-deoxy-d-glucose (2-DG) effectively suppresses spontaneous neuronal firing and epileptiform bursts in hippocampal slices. These data suggest that an altered metabolic state can profoundly affect cellular and network excitability, and that the glycolytic inhibitor 2-DG may hold promise as a novel treatment of drug-resistant epilepsy.

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Section: Discussionmentioning

confidence: 99%

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

Shao

Stafstrom

2017

Journal of Neurophysiology

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“…Perhaps this universal presence of ATP in secretory vesicles suggests that ATP might also be important for functions different from those it performs as a neurotransmitter. It has been suggested that vesicular ATP might be important for acidification of the vesicle lumen (Sperlagh & Vizi, 1996) or for fueling neurotransmitter uptake mechanisms (Takeda & Ueda, 2012). As discussed, other adenine nucleotides can also be accumulated in synaptic vesicles.…”

Section: Storage Of Purines In Synaptic Vesiclesmentioning

confidence: 99%

The purinergic neurotransmitter revisited: A single substance or multiple players?

Mutafova‐Yambolieva

Durnin

2014

Pharmacology & Therapeutics

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The past half century has witnessed tremendous advances in our understanding of extracellular purinergic signaling pathways. Purinergic neurotransmission, in particular, has emerged as a key contributor in the efficient control mechanisms in the nervous system. The identity of the purine neurotransmitter, however, remains controversial. Identifying it is difficult because purines are present in all cell types, have a large variety of cell sources, and are released via numerous pathways. Moreover, studies on purinergic neurotransmission have relied heavily on indirect measurements of integrated postjunctional responses that do not provide direct information for neurotransmitter identity. This paper discusses experimental support for adenosine 5′-triphosphate (ATP) as a neurotransmitter and recent evidence for possible contribution of other purines, in addition to or instead of ATP, in chemical neurotransmission in the peripheral, enteric and central nervous systems. Sites of release and action of purines in model systems such as vas deferens, blood vessels, urinary bladder and chromaffin cells are discussed. This is preceded by a brief discussion of studies demonstrating storage of purines in synaptic vesicles. We examine recent evidence for cell type targets (e.g., smooth muscle cells, interstitial cells, neurons and glia) for purine neurotransmitters in different systems. This is followed by brief discussion of mechanisms of terminating the action of purine neurotransmitters, including extracellular nucleotide hydrolysis and possible salvage and reuptake in the cell. The significance of direct neurotransmitter release measurements is highlighted. Possibilities for involvement of multiple purines (e.g., ATP, ADP, NAD+, ADP-ribose, adenosine, and diadenosine polyphosphates) in neurotransmission are considered throughout.

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Antiseizure effect of 2-deoxyglucose is not dependent on the presynaptic vacuole ATP pump or the somatic ATP-sensitive K⁺ channel

Shao

Janicot

Stafstrom

2023

Journal of Neurophysiology

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Inhibition of glycolysis with 2-deoxyglucose (2-DG) produces anti-seizure effects in brain slices and animal models, yet the mechanisms remain elusive. Here, we examined two glycolysis-derived ATP-associated mechanisms: vacuole ATP pump (V-ATPase) and ATP-sensitive K+ channel (KATP). Epileptiform bursts were generated in the CA3 area of hippocampal slices by 0 Mg2+ and 4-aminopyridine. 2-DG consistently abolished epileptiform bursts in the presence of pyruvate (to sustain tricarboxylic acid cycle for oxidative ATP production) at 30-33oC but not at room temperature (22oC). Under physiological conditions, 2-DG did not reduce the amplitude of evoked excitatory postsynaptic currents (EPSCs) or the paired-pulse ratio in CA3 neurons. During repetitive high-frequency (20 Hz, 20-50 pulses) stimulation, 2-DG did not accelerate the decline of EPSCs (i.e., depletion of transmitter release), even when preincubated with 8 mM K+ to enhance activity-dependent uptake of 2-DG. In addition, in 2-DG, tetanic stimulation (200 Hz, 1 s) dramatically increased rather than diminished the occurrence of spontaneous EPSCs immediately post stimulation (i.e., no transmitter depletion). Moreover, a V-ATPase blocker, concanamycin, failed to block epileptiform bursts that were subsequently abolished by 2-DG. Furthermore, 2-DG did not induce detectable KATP current in hippocampal neurons. Finally, epileptiform bursts were not affected by either a KATP opener (diazoxide) or a KATP blocker (glibenclamide) but were blocked by 2-DG in the same slices. Altogether, these data suggest that 2-DG's anti-seizure action is temperature dependent and achieved exclusively by inhibition of glycolysis, and is not likely to be mediated by the two membrane-bound ATP-associated machinery mechanisms: V-ATPase or KATP.

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Enhanced Glutamate Uptake into Synaptic Vesicles Fueled by Vesicle-generated ATP from Phosphoenolpyruvate and ADP

Cited by 3 publications

References 42 publications

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

The purinergic neurotransmitter revisited: A single substance or multiple players?

Antiseizure effect of 2-deoxyglucose is not dependent on the presynaptic vacuole ATP pump or the somatic ATP-sensitive K⁺ channel

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Enhanced Glutamate Uptake into Synaptic Vesicles Fueled by Vesicle-generated ATP from Phosphoenolpyruvate and ADP

Cited by 3 publications

References 42 publications

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

The purinergic neurotransmitter revisited: A single substance or multiple players?

Antiseizure effect of 2-deoxyglucose is not dependent on the presynaptic vacuole ATP pump or the somatic ATP-sensitive K+ channel

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Antiseizure effect of 2-deoxyglucose is not dependent on the presynaptic vacuole ATP pump or the somatic ATP-sensitive K⁺ channel