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  • Title: Extracellular metabolism of 3',5'-cyclic AMP as a source of interstitial adenosine in the rat airways.
    Author: Pacini ESA, Jackson EK, Godinho RO.
    Journal: Biochem Pharmacol; 2021 Oct; 192():114713. PubMed ID: 34331910.
    Abstract:
    In the respiratory tract, intracellular 3',5'-cAMP mediates smooth muscle relaxation triggered by the β2-adrenoceptor/Gs protein/adenylyl cyclase axis. More recently, we have shown that β2-adrenoceptor agonists also increase extracellular 3',5'-cAMP levels in isolated rat trachea, which leads to contraction of airway smooth muscle. In many other tissues, extracellular 3',5'-cAMP is metabolized by ectoenzymes to extracellular adenosine, a catabolic pathway that has never been addressed in airways. In order to evaluate the possible extracellular degradation of 3',5'-cAMP into 5'-AMP and adenosine in the airways, isolated rat tracheas were incubated with exogenous 3',5'-cAMP and the amount of 5'-AMP, adenosine and inosine (adenosine metabolite) produced was evaluated using ultraperformance liquid chromatography-tandem mass spectrometry. Incubation of tracheal tissue with 3',5'-cAMP induced a time- and concentration-dependent increase in 5'-AMP, adenosine and inosine in the medium. Importantly, IBMX (non-selective phosphodiesterase (PDE) inhibitor) and DPSPX (selective ecto-PDE inhibitor) reduced the extracellular conversion of 3',5'-cAMP to 5'-AMP. In addition, incubation of 3',5'-cAMP in the presence of AMPCP (inhibitor of ecto-5'-nucleotidase) increased extracellular levels of 5'-AMP while drastically reducing extracellular levels of adenosine and inosine. These results indicate that airways express an extracellular enzymatic system (ecto-phosphodiesterase, ecto-5'-nucleotidase and adenosine deaminase) that sequentially converts 3',5'-cAMP into 5'-AMP, adenosine and inosine. The observation that extracellular 3',5'-cAMP is a source of interstitial adenosine supports the idea that the extrusion and extracellular metabolism of 3',5'-cAMP has a role in respiratory physiology and pathophysiology.
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