Relative contribution of ecto‐ATPase and ecto‐ATPDase pathways to the biphasic effect of ATP on acetylcholine release from myenteric motoneurons

Duarte‐Araújo, Margarida; Nascimento, Carlos; Timóteo, M. Alexandrina; Magalhães-Cardoso, M.T.; Correia-de-Sá, Paulo

doi:10.1111/j.1476-5381.2008.00058.x

Cited by 39 publications

(47 citation statements)

References 53 publications

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“…Given our previous findings suggesting that excitatory A 2A receptors are preferentially activated by adenosine formed from released adenine nucleotides in rat hippocampal, neuromuscular and myenteric synapses [31,41], we evaluated the amount and distribution of ecto-5′-nucleotidase/CD73 in the human hippocampus compared to those of the A 2A receptor, as this is the rate limiting enzyme for extracellular adenosine formation in the brain. Figure 5a shows that the hippocampus of MTLE patients exhibits higher (P < 0.001) amounts of ecto-5′-nucleotidase/CD73 protein (∼55 kDa) than control individuals.…”

Section: Resultsmentioning

confidence: 99%

“…This may be critical for A 2A receptor activation because adenosine resulting from the extracellular catabolism of released ATP, via the ecto-5′-nucleotidase/ CD73 pathway, preferentially activates this receptor subtype in the hippocampus and other excitatory synapses (e.g., neuromuscular junction, myenteric plexus) [31,41]. The tight association between ecto-5′-nucleotidase/CD73 and the A 2A receptor has been elegantly and definitively documented by co-immunoprecipitation and proximity ligation assays in the striatum [45].…”

Section: Discussionmentioning

confidence: 99%

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Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Barros‐Barbosa

Ferreirinha

Oliveira

et al. 2016

Purinergic Signalling

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Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A 2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A 1 receptors. Gain of function of the excitatory A 2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity. Here, we investigated changes in the expression and cellular localization of the A 2A receptor and of the adenosine-generating enzyme, ecto-5′-nucleotidase/ CD73, in the hippocampus of control individuals and MTLE human patients. Western blot analysis indicates that the A 2A receptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A 2A receptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No colocalization was observed between the A 2A receptor and neuronal cell markers, like synaptotagmin 1/2 (nerve terminals) and neurofilament 200 (axon fibers). Hippocampal astrogliosis observed in MTLE patients was accompanied by a proportionate increase in A 2A receptor and ecto-5′-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A 2A receptors and/or inhibition of surplus adenosine formation by membrane-bound ecto-5′-nucleotidase/CD73 may reduce neuronal excitability, thus providing a novel therapeutic target for drug-refractory seizures in MTLE patients. • Ecto-5′-nucleotidase/CD73 localizes in close proximity with adenosine A 2A receptors in astrocytes of the human hippocampus. Keywords Mesial temporal lobe epilepsy (MTLE• Up-regulation of A 2A receptors and ecto-5′-nucleotidase/CD73 associates with astrogliosis of the hippocampus of MTLE patients.• Targeting astrocytic A 2A activation and/or adenosine formation via ecto-5′-nucleotidase/CD73 may control neuronal excitability.• Inhibitors of astrocytic A 2A receptors and ecto-5′-nucleotidase/CD73 may be a novel therapeutic strategy to control drug-refractory MTLE.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Barros‐Barbosa

Ferreirinha

Oliveira

et al. 2016

Purinergic Signalling

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“…Morphological data on P2 receptor distribution in the gut are scarce. At least in the mouse ileum, smooth muscle cells were strongly immunoreactive for P2Y 1 receptors [7] , and myenteric plexus neurons in the guinea-pig ileum were shown to express the P2Y 6 and P2Y 12 receptor [36] . However, interspecies differences are very likely, because α,β-Me-ATP-induced contractions of guinea-pig ileum were sensitive to the P2X 1 receptor antagonist NF279 and the P2X receptor-preferring blocker PPADS [37] .…”

Section: Wwwchinapharcom Mader F Et Almentioning

confidence: 99%

“…Post-junctional P2Y receptors, however, activate apamin-sensitive SK channels as a consequence of Ca 2+ release from thapsigargin-sensitive stores and thus promote relaxation [4,9,19,20] . Recently, an elegant study tested the hypothesis that spontaneous hydrolysis products of ATP, such as ADP and adenosine, mediate the biphasic effects observed following ATP administration and found that ADP and adenosine were agonists of P2Y and adenosine A 1 receptor, respectively, thereby having the opposite effects from ATP [6] .…”

Section: Introductionmentioning

confidence: 99%

“…While NO leads to a long-lasting inhibition of smooth muscle motility, the available data on purinergic responses are less consistent, as both excitatory and inhibitory effects have been observed and seem to depend on the subtype and cellular location of P2 purinoceptors. In addition, species differences should also be considered [2][3][4][5][6][7][8][9][10] . Seven cloned ionotropic P2X receptors that combine heteromerically, as well as eight cloned metabotropic P2Y receptors, account for the large heterogeneity of purinoceptormediated effects [11] .…”

Section: Introductionmentioning

confidence: 99%

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P2Y receptor-mediated transient relaxation of rat longitudinal ileum preparations involves phospholipase C activation, intracellular Ca2+ release and SK channel activation

et al. 2016

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Aim: Purinergic signaling plays a major role in the enteric nervous system, where it governs gut motility through a number of P2X and P2Y receptors. The aim of this study was to investigate the P2Y receptor-mediated motility in rat longitudinal ileum preparations. Methods: Ileum smooth muscle strips were prepared from rats, and fixed in an organ bath. Isometric contraction and relaxation responses of the muscle strips were measured with force transducers. Drugs were applied by adding of stock solutions to the organ bath to yield the individual final concentrations. Results: Application of the non-hydrolyzable P2 receptor agonists α,β-Me-ATP or 2-Me-S-ADP (10, 100 µmol/L) dose-dependently elicited a transient relaxation response followed by a sustained contraction. The relaxation response was largely blocked by SK channel blockers apamin (500 nmol/L) and UCL1684 (10 µmol/L), PLC inhibitor U73122 (100 µmol/L), IP 3 receptor blocker 2-APB (100 µmol/L) or sarcoendoplasmic Ca 2+ ATPase inhibitor thapsigargin (1 µmol/L), but not affected by atropine, NO synthase blocker L-NAME or tetrodotoxin. Furthermore, α,β-Me-ATP-induced relaxation was suppressed by P2Y 1 receptor antagonist MRS2179 (50 µmol/L) or P2Y 13 receptor antagonist MRS2211 (100 µmol/L), and was abolished by co-application of the two antagonists, whereas 2-Me-S-ADP-induced relaxation was abolished by P2Y 6 receptor antagonist MRS2578 (50 µmol/L). In addition, P2Y 1 receptor antagonist MRS2500 (1 µmol/L) not only abolished α,β-Me-ATP-induced relaxation, but also suppressed 2-Me-S-ADP-induced relaxation. Conclusion: P2Y receptor agonist-induced transient relaxation of rat ileum smooth muscle strips is mediated predominantly by P2Y 1 receptor, but also by P2Y 6 and P2Y 13 receptors, and involves PLC, IP 3 , Ca 2+ release and SK channel activation, but is independent of acetylcholine and NO release.

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P2X receptors in the gut

Burnstock

2011

WIREs Membr Transp Signal

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Purinergic transmission, which uses ATP and its derivatives as extracellular signaling molecules, is widely distributed throughout all tissues and systems, including the gastrointestinal system. Ionotropic P2X purinoceptors have been identified in various parts of the enteric nervous system, including myenteric, submucosal motor, sensory, and secretomotor neurones, in enteric glial cells and interstitial cells of Cajal. Purinergic mechanosensory transduction, where there is release of ATP from mucosal epithelial cells during distension, stimulating subepithelial nerve endings of intrinsic and extrinsic sensory nerves to modulate peristalsis and initiate nociception. Purinergic signaling in the gut is involved in development, aging, and regeneration of the gut, and the pathophysiology of enteric purinergic signaling in diseases including irritable bowel syndrome, postoperative ileus, esophageal reflux, constipation, diarrhea, diabetes, Chaga's and Hirschprung's diseases.Myenteric neurons have been classified into two groups: Dogiel Type I/S neurons (which are motor neurons or interneurons) and Dogiel Type II/AH neurons (which are sensory neurons). ATP-induced hyperpolarizations reduced excitability of AH neurons, while ATP-induced depolarization increased excitability of most S neurons. 9 Later it was shown that ATP mediates fast synaptic potentials in enteric neurons. 22 P2X receptors mediated fast excitatory postsynaptic currents in guinea pig cultured myenteric neurons; these neurons express both fast-desensitizing α,β-methylene ATP (α,β-meATP)-sensitive P2X 1 -like receptors and slow-desensitizing α,β-meATP-insensitive P2X 2 -like receptors. 23 P2X 2 receptors were considered to be the dominant P2X receptor in cultured rat myenteric neurons. 24 In another study of guinea pig myenteric neurons, it was concluded that the P2X receptors on the neurons shared properties with P2X 4 and P2X 6 receptors. 25 ATP elevates [Ca 2+ ] i via P2 receptors in cultured Type II/AH neurons from adult guinea pigs' small intestine. 26 Fast excitatory postsynaptic potentials (EPSPs) mediated, at least in apart, via P2X receptors, are predominant in myenteric neurons along the small and large intestines of guinea pigs, but are rare in the gastric corpus. 27 Volume 1,

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Relative contribution of ecto‐ATPase and ecto‐ATPDase pathways to the biphasic effect of ATP on acetylcholine release from myenteric motoneurons

Cited by 39 publications

References 53 publications

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

P2Y receptor-mediated transient relaxation of rat longitudinal ileum preparations involves phospholipase C activation, intracellular Ca2+ release and SK channel activation

P2X receptors in the gut

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