Extracellular metabolism of ATP and other nucleotides

Zimmermann, Herbert

doi:10.1007/s002100000309

Cited by 881 publications

(840 citation statements)

References 105 publications

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“…Extracellular concentrations of adenosine are regulated by direct release from cells (Melani et al, 2012), extracellular metabolism of released ATP (Zimmermann, 2000) and reuptake into cells followed by intracellular metabolism (Bender and Hertz, 1986). Adenosine is principally metabolized in the CNS by adenosine kinase, an enzyme expressed in highest concentrations in astrocytes (Studer et al, 2006).…”

Section: The Role Of Adenosine In Neuroinflammationmentioning

confidence: 99%

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

et al. 2016

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a b s t r a c tThe principle functions of neuroinflammation are to limit tissue damage and promote tissue repair in response to pathogens or injury. While neuroinflammation has utility, pathophysiological inflammatory responses, to some extent, underlie almost all neuropathology. Understanding the mechanisms that control the three stages of inflammation (initiation, propagation and resolution) is therefore of critical importance for developing treatments for diseases of the central nervous system. The purinergic signaling system, involving adenosine, ATP and other purines, plus a host of P1 and P2 receptor subtypes, controls inflammatory responses in complex ways. Activation of the inflammasome, leading to release of pro-inflammatory cytokines, activation and migration of microglia and altered astroglial function are key regulators of the neuroinflammatory response. Here, we review the role of P1 and P2 receptors in mediating these processes and examine their contribution to disorders of the nervous system. Firstly, we give an overview of the concept of neuroinflammation. We then discuss the contribution of P2X, P2Y and P1 receptors to the underlying processes, including a discussion of cross-talk between these different pathways. Finally, we give an overview of the current understanding of purinergic contributions to neuroinflammation in the context of specific disorders of the central nervous system, with special emphasis on neuropsychiatric disorders, characterized by chronic low grade inflammation or maternal inflammation. An understanding of the important purinergic contribution to neuroinflammation underlying neuropathology is likely to be a necessary step towards the development of effective interventions.

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Section: The Role Of Adenosine In Neuroinflammationmentioning

confidence: 99%

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

et al. 2016

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“…Extracellular ATP is then cleaved into adenosine by a cascade of ectonucleotidases (Cunha, 2001;Zimmermann, 2000). The presynaptic release of ATP and its extracellular conversion to adenosine has important consequences for the modulation of synaptic transmission.…”

Section: Presynaptic Vesicular Release Of Atpmentioning

confidence: 99%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

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Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and -finally -to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

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“…Extracellular, and thus synaptic, adenosine appears to be largely under the control of an astrocyte-based adenosine cycle (Boison, 2008a) that involves regulated release of ATP (Pascual et al, 2005), extracellular degradation of ATP to adenosine (Zimmermann, 2000), equilibration of extra-and intracellular pools of adenosine via nucleoside transporters (Baldwin et al, 2004;Gray et al, 2004), and intracellular phosphorylation of adenosine to AMP via adenosine kinase (ADK) (Boison, 2006). ADK functions largely as a metabolic reuptake system for adenosine, driving the influx of adenosine into the cell (Boison, 2006).…”

Section: Introductionmentioning

confidence: 99%

Adenosine dysfunction in astrogliosis: cause for seizure generation?

et al. 2007

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Epilepsy is characterized by both neuronal and astroglial dysfunction. The endogenous anticonvulsant adenosine, the level of which is largely controlled by astrocytes, might provide a critical link between astrocyte and neuron dysfunction in epilepsy. Here we studied astrogliosis, a hallmark of the epileptic brain, adenosine dysfunction and the emergence of spontaneous seizures in a comprehensive approach including a new mouse model of focal epileptogenesis, mutant mice with altered brain levels of adenosine, and mice lacking adenosine A 1 receptors. In wild type mice, following a focal epileptogenesis-precipitating injury, astrogliosis, upregulation of the adenosineremoving astrocytic enzyme adenosine kinase (ADK), and spontaneous seizures all coincided in a spatio-temporally restricted manner. Importantly, these spontaneous seizures were mimicked in untreated transgenic mice overexpressing ADK in brain or those lacking A 1 receptors. Conversely, mice with reduced forebrain ADK did not develop astrogliosis or spontaneous seizures. Our studies define ADK as critical upstream regulator of A 1 receptor mediated modulation of neuronal excitability and support the ADK hypothesis of epileptogenesis implicating that upregulation of ADK during astrogliosis provides a critical link between astrocyte and neuron dysfunction in epilepsy. These findings define ADK as rational target for therapeutic intervention.

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Extracellular metabolism of ATP and other nucleotides

Cited by 881 publications

References 105 publications

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

The adenosine kinase hypothesis of epileptogenesis

Adenosine dysfunction in astrogliosis: cause for seizure generation?

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