Deletion of Ecto-5′-Nucleotidase (<i>CD73</i>) Reveals Direct Action Potential-Dependent Adenosine Release

Klyuch, Boris P.; Dale, Nicholas; Wall, Mark J.

doi:10.1523/jneurosci.6052-11.2012

Cited by 59 publications

(82 citation statements)

References 22 publications

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“…In studies of CD73 −/− mice deficient in ectonucleotidase, dependence on ATP breakdown and ionotropic glutamate receptors was correlated [17], indicating they were the same mechanism. In our studies, evoked adenosine was both ATP and glutamate receptor dependent in the nucleus accumbens, demonstrating that more than one mechanism can occur in a region.…”

Section: Discussionmentioning

confidence: 95%

“…Thus, exocytosis of another neurotransmitter such as glutamate causes downstream release of adenosine, although the mechanism of that release is unknown. Using enzymatic biosensors, a portion of evoked adenosine release in the cerebellum is AMPA receptor dependent in mice [17] but not in rats [31]. Therefore, the dependence of evoked adenosine release on glutamate receptors varies by brain region and species.…”

Section: Discussionmentioning

confidence: 99%

“…For slower adenosine changes, the accepted mechanisms of extracellular adenosine formation are transport of adenosine out of a cell by nucleoside transporters and the breakdown of ATP in the extracellular space after it is released by exocytosis or through hemichannels [14][15][16]. However, there is evidence that rapid adenosine release can also be due to downstream effects of activation of other neurons [6] or direct exocytosis of adenosine [17], but these mechanisms differ between species and brain regions.…”

Section: Introductionmentioning

confidence: 99%

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The mechanism of electrically stimulated adenosine release varies by brain region

Pajski

Venton

2012

Purinergic Signalling

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Adenosine plays an important role in neuromodulation and neuroprotection. Recent identification of transient changes in adenosine concentration suggests adenosine may have a rapid modulatory role; however, the extent of these changes throughout the brain is not well understood. In this report, transient changes in adenosine evoked by one second, 60 Hz electrical stimulation trains were compared in the caudate-putamen, nucleus accumbens, hippocampus, and cortex. The concentration of evoked adenosine varies between brain regions, but there is less variation in the duration of signaling. The highest concentration of adenosine was evoked in the dorsal caudate-putamen (0.34± 0.08 μM), while the lowest concentration was in the secondary motor cortex (0.06±0.02 μM). In all brain regions, adenosine release was activity-dependent. In the nucleus accumbens, hippocampus, and prefrontal cortex, this release was partly due to extracellular ATP breakdown. However, in the caudate-putamen, release was not due to ATP metabolism but was ionotropic glutamate receptor-dependent. The results demonstrate that transient, activity-dependent adenosine can be evoked in many brain regions but that the mechanism of formation and release varies by region.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mechanism of electrically stimulated adenosine release varies by brain region

Pajski

Venton

2012

Purinergic Signalling

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“…There is considerable evidence for neuromodulatory functions of nucleosides. Adenosine and Guo can be released from synaptosomes [44][45][46][47][48][49] and may then bind to their specific receptors [32,50,51]; thus, Ado, Guo and most likely Urd [52] may be signaling molecules (neuromodulators or neurotransmitters) in the brain. Area-, age-and genderdependence of nucleoside levels and/or nucleoside metabolism, nucleoside transporters and nucleoside receptors in the brain have been described previously, suggesting that nucleosides have different physiological and pathophysiological Fig.…”

Section: Introductionmentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

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“…54 Another source of extracellular adenosine is ATP, which can be released from cells either by vesicular exocytosis or through specific transmembrane channels, followed by conversion of ATP to adenosine in the extracellular space. [54][55][56][57][58][59] Adenosine facilitates sleep in part through binding to the neuronal G proteincoupled adenosine receptors. Recent evidence strongly suggests a role for extracellular adenosine as an endogenous somnogen.…”

Section: Introductionmentioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

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Deletion of Ecto-5′-Nucleotidase (CD73) Reveals Direct Action Potential-Dependent Adenosine Release

Cited by 59 publications

References 22 publications

The mechanism of electrically stimulated adenosine release varies by brain region

The mechanism of electrically stimulated adenosine release varies by brain region

The Antiepileptic Potential of Nucleosides

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

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