title: Feed-forward inhibition of CD73 and upregulation of adenosine deaminase contribute to the loss of adenosine neuromodulation in postinflammatory ileitis.
abstract: Purinergic signalling is remarkably plastic during gastrointestinal inflammation. Thus, selective drugs targeting the "purinome" may be helpful for inflammatory gastrointestinal diseases. The myenteric neuromuscular transmission of healthy individuals is fine-tuned and controlled by adenosine acting on A(2A) excitatory receptors. Here, we investigated the neuromodulatory role of adenosine in TNBS-inflamed longitudinal muscle-myenteric plexus of the rat ileum. Seven-day postinflammation ileitis lacks adenosine neuromodulation, which may contribute to acceleration of gastrointestinal transit. The loss of adenosine neuromodulation results from deficient accumulation of the nucleoside at the myenteric synapse despite the fact that the increases in ATP release were observed. Disparity between ATP outflow and adenosine deficit in postinflammatory ileitis is ascribed to feed-forward inhibition of ecto-5'-nucleotidase/CD73 by high extracellular ATP and/or ADP. Redistribution of NTPDase2, but not of NTPDase3, from ganglion cell bodies to myenteric nerve terminals leads to preferential ADP accumulation from released ATP, thus contributing to the prolonged inhibition of muscle-bound ecto-5'-nucleotidase/CD73 and to the delay of adenosine formation at the inflamed neuromuscular synapse. On the other hand, depression of endogenous adenosine accumulation may also occur due to enhancement of adenosine deaminase activity. Both membrane-bound and soluble forms of ecto-5'-nucleotidase/CD73 and adenosine deaminase were detected in the inflamed myenteric plexus. These findings provide novel therapeutic targets for inflammatory gut motility disorders.
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), L. Prof. Abel Salazar 2, 4099-033 Porto, Portugal.
authors.forename: Cátia
authors.identifier: 0000-0002-0619-8527
authors.initials: C
authors.lastname: Vieira
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), L. Prof. Abel Salazar 2, 4099-033 Porto, Portugal.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Magalhães-Cardoso
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), L. Prof. Abel Salazar 2, 4099-033 Porto, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Ferreirinha
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), L. Prof. Abel Salazar 2, 4099-033 Porto, Portugal.
authors.forename: Isabel
authors.identifier: 0000-0001-7244-4792
authors.initials: I
authors.lastname: Silva
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), L. Prof. Abel Salazar 2, 4099-033 Porto, Portugal.
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Dias
authors.affiliation: Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2.
authors.forename: Julie
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Centre de Recherche du CHU de Québec, CHUL, Québec, QC, Canada G1V 4G2 ; Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, Québec, QC, Canada G1V 0A6.
authors.forename: Jean
authors.identifier: 0000-0003-2922-1600
authors.initials: J
authors.lastname: Sévigny
authors.affiliation: Laboratório de Farmacologia e Neurobiologia, UMIB and MedInUP, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), L. Prof. Abel Salazar 2, 4099-033 Porto, Portugal.
authors.forename: Paulo
authors.identifier: 0000-0002-6114-9189
authors.initials: P
authors.lastname: Correia-de-Sá
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000378:metabolism*; D000818:Animals; D005260:Female; D007079:Ileitis / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D051381:Rats; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: D014302:Trinitrobenzenesulfonic Acid; D015720:5'-Nucleotidase; D000243:Adenosine Deaminase; D000241:Adenosine