Ecto-ATPase inhibition: ATP and adenosine release under physiological and ischemic in vivo conditions in the rat striatum

Melani, Alessia; Corti, Francesca; Stephan, Holger; Müller, Christian; Donati, Chiara; Bruni, Paola; Vannucchi, Maria Giuliana; Pedata, Felicita

doi:10.1016/j.expneurol.2011.09.036

Cited by 87 publications

(68 citation statements)

References 78 publications

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“…Data on nucleotide concentrations actually occurring in situ in resting or activated tissue are scarce. Using microdialysis techniques, the interstitial concentration of ATP in living rat brain (striatum) was estimated to be in the range of 30 nM [358], which comes close to the EC 50 value of some P2YRs. Inhibiting ectonucleotidases raised the ATP concentrations to 260 nM, which would still be too low to efficiently activate P2XRs.…”

Section: Discussionmentioning

confidence: 66%

Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

Zimmermann

2015

Purinergic Signalling

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Extracellular nucleotides, and ATP in particular, are cellular signal substances involved in the control of numerous (patho)physiological mechanisms. They provoke nucleotide receptor-mediated mechanisms in select target cells. But nucleotides can considerably expand their range of action. They function as primary messengers in intercellular communication by stimulating the release of other extracellular messenger substances. These in turn activate additional cellular mechanisms through their own receptors. While this applies also to other extracellular messengers, its omnipresence in the vertebrate organism is an outstanding feature of nucleotide signaling. Intercellular messenger substances released by nucleotides include neurotransmitters, hormones, growth factors, a considerable variety of other proteins including enzymes, numerous cytokines, lipid mediators, nitric oxide, and reactive oxygen species. Moreover, nucleotides activate or co-activate growth factor receptors. In the case of hormone release, the initially paracrine or autocrine nucleotide-mediated signal spreads through to the entire organism. The examples highlighted in this commentary suggest that acting as ubiquitous triggers of intercellular messenger release is one of the major functional roles of extracellular nucleotides. While initiation of messenger release by nucleotides has been unraveled in many contexts, it may have been overlooked in others. It can be anticipated that additional nucleotide-driven messenger functions will be uncovered with relevance for both understanding physiology and development of therapy.

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Section: Discussionmentioning

confidence: 66%

Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

Zimmermann

2015

Purinergic Signalling

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“…Like other neurotransmitters, the exocytosis of adenosine would require some form of vesicular transporter to fill the vesicles with adenosine. Recent evidence suggests that adenosine concentrative transporters are present on synaptic vesicles in the striatum (Melani et al, 2012) but because they are Na ϩ -dependent they may not play a role in vesicular filling. The identification of a vesicular adenosine transporter and its mechanism of action will be a priority of future work.…”

Section: Discussionmentioning

confidence: 99%

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

Klyuch¹,

Dale²,

Wall³

2012

J. Neurosci.

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Purinergic signaling is a highly complex system of extracellular communication involved in many physiological and pathological functions in the mammalian brain. Its complexity stems from the multitude of purine receptor subtypes and endogenous purine receptor ligands (including ATP, ADP, UTP, UDP, and adenosine). Potentially all of these ligands could be directly released, and some could also arise from extracellular metabolism. A widely held consensus is that, except under pathological conditions, extracellular adenosine arises only from ectoATPase-mediated metabolism of previously released ATP. Here, we have used mice that lack the CD73 gene (encoding ecto-5Ј-nucleotidase that converts AMP to adenosine) to test whether action potential-dependent adenosine release in the cerebellum depends on prior ATP release. Surprisingly, we have uncovered two parallel pathways of adenosine release: one that is indirect via glutamate receptor-dependent release of ATP and a second of equal amplitude that has no dependence on prior release of ATP and thus represents the direct release of adenosine. This component of adenosine release is blocked by bafilomycin and modulated by mGlu4 receptor activation, strongly supporting adenosine release by exocytosis from parallel fibers. Our findings are a major step in understanding the mechanisms of adenosine release and are likely to have implications for all aspects of physiology where adenosine plays a key modulatory role.

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“…eATP is now recognized as an important signaling molecule that initiates an array of physiological responses, including neurotransmission, immune cell recruitment, regulation of vascular and muscular tone, and perception of pain through the activation of cell surface P2 receptors (8,18,74,85,92,95). Under normal conditions, the concentration of eATP, the endogenous P2X7R agonist, is tightly regulated by ecto-ATPases that rapidly hydrolyze eATP (16,52,55). However, in the event of tissue damage, disease, or stress, the concentration of eATP rises significantly resulting in cell death by either necrosis or apoptosis, depending on the magnitude and location of ATP release (18).…”

Section: Discussionmentioning

confidence: 99%

P2X7 receptor activation induces inflammatory responses in salivary gland epithelium

Woods

Camden

Batek

et al. 2012

American Journal of Physiology-Cell Physiology

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Inflammation of the salivary gland is a well-documented aspect of salivary gland dysfunction that occurs in Sjogren's syndrome (SS), an autoimmune disease, and in γ-radiation-induced injury during treatment of head and neck cancers. Extracellular nucleotides have gained recognition as key modulators of inflammation through activation of cell surface ionotropic and metabotropic receptors, although the contribution of extracellular nucleotides to salivary gland inflammation is not well understood. In vitro studies using submandibular gland (SMG) cell aggregates isolated from wild-type C57BL/6 mice indicate that treatment with ATP or the high affinity P2X7R agonist 3'-O-(4-benzoyl)benzoyl-ATP (BzATP) induces membrane blebbing and enhances caspase activity, responses that were absent in SMG cell aggregates isolated from mice lacking the P2X7R (P2X7R(-/-)). Additional studies with SMG cell aggregates indicate that activation of the P2X7R with ATP or BzATP stimulates the cleavage and release of α-fodrin, a cytoskeletal protein thought to act as an autoantigen in the development of SS. In vivo administration of BzATP to ligated SMG excretory ducts enhances immune cell infiltration into the gland and initiates apoptosis of salivary epithelial cells in wild-type, but not P2X7R(-/-), mice. These findings indicate that activation of the P2X7R contributes to salivary gland inflammation in vivo, suggesting that the P2X7R may represent a novel target for the treatment of salivary gland dysfunction.

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Ecto-ATPase inhibition: ATP and adenosine release under physiological and ischemic in vivo conditions in the rat striatum

Cited by 87 publications

References 78 publications

Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

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

P2X7 receptor activation induces inflammatory responses in salivary gland epithelium

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