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Ecto-AMP deaminase blunts the ATP-derived adenosine A_2A receptor facilitation of acetylcholine release at rat motor nerve endings

M. Teresa Magalhães-Cardoso*, M. Fátima Pereira†, Laura Oliveira*, J. A. Ribeiro†, Rodrigo A. Cunha‡ and Paulo Correia-de-Sá*

At synapses, ATP is released and metabolised through ecto-nucleotidases forming adenosine, which modulates neurotransmitter release through inhibitory A₁ or facilitatory A_2A receptors, according to the amounts of extracellular adenosine. Neuromuscular junctions possess an ecto-AMP deaminase that can dissociate extracellular ATP catabolism from adenosine formation. In this study we have investigated the pattern of ATP release and its conversion into adenosine, to probe the role of ecto-AMP deaminase in controlling acetylcholine release from rat phrenic nerve terminals. Nerve-evoked ATP release was 28 ± 12 pmol (mg tissue)^-1 at 1 Hz, 54 ± 3 pmol (mg tissue)^-1 at 5 Hz and disproportionally higher at 50 Hz (324 ± 23 pmol (mg tissue)^-1). Extracellular ATP (30 µM) was metabolised with a half time of 8 ± 2 min, being converted into ADP then into AMP. AMP was either dephosphorylated into adenosine by ecto-5'-nucleotidase (inhibited by ATP and blocked by 200 µM ,-methylene ADP) or deaminated into IMP by ecto-AMP deaminase (inhibited by 200 µM deoxycoformycin, which increased adenosine formation). Dephosphorylation and deamination pathways also catabolised endogenously released adenine nucleotides, since the nerve-evoked extracellular AMP accumulation was increased by either ,-methylene ADP (200 µM) or deoxycoformycin (200 µM). In the presence of nitrobenzylthioinosine (30 µM) to inhibit adenosine transport, deoxycoformycin (200 µM) facilitated nerve-evoked [³H]acetylcholine release by 77 ± 9 %, an effect prevented by the A_2A receptor antagonist, ZM 241385 (10 nM). It is concluded that, while ecto-5'-nucleotidase is inhibited by released ATP, ecto-AMP deaminase activity transiently blunts adenosine formation, which would otherwise reach levels high enough to activate facilitatory A_2A receptors on motor nerve terminals.

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