Purinergic P2 receptors trigger adenosine release leading to adenosine A2A receptor activation and facilitation of long-term potentiation in rat hippocampal slices

doi:10.1016/S0306-4522(03)00523-2

Neuroscience

Volume 122, Issue 1, 20 November 2003, Pages 111-121

https://doi.org/10.1016/S0306-4522(03)00523-2 Get rights and content

Abstract

Electrophysiological recordings were used to investigate the effects of ATP analogues on θ-burst-induced long-term potentiation (LTP) in rat hippocampal slices. α,β-Methylene ATP (α,β-MeATP; 20 μM) decreased LTP from 36±9% to 17±5%, an effect prevented by adenosine A₁ receptor blockade in accordance with the localised catabolism of ATP analogues into adenosine, leading to adenosine A₁ receptor activation. Thus, to probe the role of extracellular ATP, all experiments were performed with the A₁ receptor selective antagonist, 1,3-dipropyl-8-cyclopentylxanthine (50 nM). In these conditions, α,β-MeATP or 5′-adenylylimido-diphosphate (β,γ-ImATP; 20 μM) facilitated LTP by 120%, an effect prevented by the P2 receptor antagonists, pyridoxalphosphate-6-azophenyl-2′-4′-disulphonic acid (PPADS; 20 μM) or suramin (75 μM), as well as by the P2X_1/3-selective antagonist 8-(benzamido)naphthalene-1,3,5-trisulfonate (10 μM). The facilitations of LTP by either α,β-MeATP or β,γ-ImATP (20 μM) were also prevented by both 4-(2-[7-amino-2-(2-furyl(1,2,4)-triazolo(2,3a)-(1,3,5)triazin-5-yl-amino]ethyl)phenol (50 nM) or 7–2(-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (50 nM), antagonists of facilitatory adenosine A_2A receptors, were occluded by the A_2A receptor agonist, CGS 21680 (10 nM) and were prevented by the protein kinase C inhibitor, chelerythrine (6 μM) and unaffected by the protein kinase A inhibitor, H89 (1 μM). Furthermore, β,γ-ImATP (20 μM) enhanced [³H]adenosine outflow from rat hippocampal slices by nearly 150%, an effect prevented by PPADS (20 μM) or suramin (75 μM). The adenosine transport inhibitors, nitrobenzylthioinosine (5 μM) and dipyridamole (10 μM) also prevented β,γ-ImATP (20 μM)-induced [³H]adenosine outflow and facilitation of LTP. These results suggest that ATP analogues facilitate LTP through P2 receptor activation that mainly triggers adenosine release leading to the activation of adenosine A_2A receptors.

Section snippets

Drugs

Adenosine deaminase (type VI; 1803 U/ml; EC 3.5.4.4), S-(p-nitrobenzyl)-6-thioinosine (NBTI), α,β-methylene ATP (α,β-MeATP) and 5-adenylylimido-diphosphate (β,γ-Imido ATP) were from Sigma (Reagente 5, Porto, Portugal), 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), 8-{4-[(2-aminoethyl)amino]carbonylmethyl-oxyphenyl}xanthine (XAC), suramin, 2-[4-(2-p-carboxyethyl)phenylamino]-5′-N-ethylcarboxamidoadenosine (CGS 21680), pyridoxal phosphate-6-azophenyl-2,4-disulphonic acid (PPADS), and

ATP analogues facilitate LTP when adenosine A₁ receptors are blocked

The application of θ-burst stimulation (three trains of 100 Hz, four stimuli, separated by 200 ms) in one pathway caused LTP with an amplitude of 36.4±8.7% (n=4). The application of a similar θ-burst stimulation in the other pathway in the presence of αβ-MeATP (20 μM) elicited a smaller LTP (16.6±5.0%, n=4, P<0.05). This inhibitory effect of the ATP analog is similar to the inhibition of LTP by adenosine A₁ receptor activation (de Mendonça and Ribeiro, 1990) and it is known that, under basal

Discussion

The present results show that the modulation by extracellular ATP analogues of θ-burst-induced LTP in rat hippocampal slices requires the activation of P2 receptors, but ultimately depends on the induced release of adenosine and activation of adenosine receptors. Upon blockade of inhibitory adenosine A₁ receptors, ATP activates P2 receptors that trigger an enhanced adenosine outflow through nucleoside transporters, particularly from nerve terminals and astrocytes, and this released adenosine

Acknowledgements

This work was supported by Fundação para a Ciência e Tecnologia (POCTI/43633/1999 and POCTI/36372/1999). The authors thank I. Araújo and J. O. Malva for their help in the experiments using cultured hippocampal neurons and astrocytes.

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Extracellular adenosine levels are determined by the balance between its synthesis and degradation. In most cases adenosine is generated because of the sequential metabolic action of various ectonucleotidases (CD73, CD39) on nucleotide precursors namely, ATP, ADP, and AMP (Dos Santos-Rodrigues, Grane-Boladeras, Bicket, & Coe, 2014; Nguyen, Ross, Ryals, Lee, & Venton, 2015; Pastor-Anglada & Perez-Torras, 2018b) and sometimes released from the cells (Almeida, Rodrigues, de Mendonca, Ribeiro, & Cunha, 2003). The disposal of extracellular adenosine is mediated by either metabolism, i.e., conversion to inosine via adenosine deaminase, or by its uptake into cells followed by metabolic trapping as AMP after being phosphorylated by adenosine kinase.
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Purinergic P2 receptors trigger adenosine release leading to adenosine A2A receptor activation and facilitation of long-term potentiation in rat hippocampal slices

Abstract

Section snippets

Drugs

ATP analogues facilitate LTP when adenosine A1 receptors are blocked

Discussion

Acknowledgements

Neuropharmacology

Neurosci Lett

Brain Res

Brain Res

Neurochem Int

Life Sci

Neurosci Lett

J Biol Chem

Neurosci Lett

Neuroscience

Neuroscience

Neurosci Lett

Prog Neurobiol

Neuroscience

Neurosci Lett

Brain Res

Eur J Pharmacol

Eur J Pharmacol

Anal Biochem

Eur J Pharmacol

Neuropharmacology

Brain Res

Brain Res

Prog Brain Res

Autoradiography of P2X ATP receptors in the rat brain

Br J Pharmacol

ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord

J Neurosci

A synaptic mode of memorylong-term potentiation in the hippocampus

Nature

Distribution of [3H]-α, β-methylene ATP binding sites in rat brain and spinal cord

Neuroreport

Inhibitory avoidance learning inhibits ectonucleotidases activities in hippocampal synaptosomes of adult rats

Neurochem Res

Surface protein phosphorylation by ecto-protein kinase is required for the maintenance of hippocampal long-term potentiation

Proc Natl Acad Sci USA

Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus

J Physiol

Cloning of P2X5 and P2X6 receptors and the distribution and properties of an extended family of ATP-gated ion channels

J Neurosci

Purinergic P2 receptors trigger adenosine release leading to adenosine A_2A receptor activation and facilitation of long-term potentiation in rat hippocampal slices

ATP analogues facilitate LTP when adenosine A₁ receptors are blocked

ATP P_2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord

Distribution of [³H]-α, β-methylene ATP binding sites in rat brain and spinal cord

Cloning of P2X₅ and P2X₆ receptors and the distribution and properties of an extended family of ATP-gated ion channels