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Am. J. Respir. Cell Mol. Biol., Volume 23, Number 2, August, 2000 255-261

Biochemical Evidence for an Ecto Alkaline Phosphodiesterase I in Human Airways

Maryse Picher and Richard C. Boucher

Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina

Because dinucleotides are signaling molecules that can interact with cell surface receptors and regulate the rate of mucociliary clearance in lungs, we studied their metabolism by using human airway epithelial cells. A membrane-bound enzyme was detected on the mucosal surface of polarized epithelia that metabolized dinucleotides with a broad substrate specificity (diadenosine polyphosphates and diuridine polyphosphates [UpnU], n = 2 to 6). The enzymatic reaction yielded nucleoside monophosphates (NMP) and Npn-1 (N = A or U), and was inhibited by nucleoside 5'-triphosphates (alpha ,beta met adenosine triphosphate [ATP] > ATP >=  uridine triphosphate > guanidine triphosphate > cytidine triphosphate). The apparent Michaelis constant (Km,app) and apparent maximal velocity (Vmax,app) for [3H]Up4U were 22 ± 4 µM and 0.24 ± 0.05 nmoles · min-1 · cm-2, respectively. Thymidine 5'-monophosphate p-nitrophenyl ester and adenosine diphosphate (ADP)- ribose, substrates of ecto alkaline phosphodiesterase I (PDE I) activities, were also hydrolyzed by the apical surface of airway epithelia. ADP-ribose competed with [3H]Up4U, with a Ki of 23 ± 3 µM. The metabolism of ADP-ribose and Ap4A was not affected by inhibitors of cyclic nucleotide phosphodiesterases (3-isobutyl-1-methylxanthine, Ro 20-1724, and 1,3-dipropyl-8-p-sulfophenylxanthine), but similarly inhibited by fluoride and N-ethylmaleimide. These results suggest that a PDE I is responsible for the hydrolysis of extracellular dinucleotides in human airways. The wide substrate specificity of PDE I suggests that it may be involved in several signaling events on the luminal surface of airway epithelia, including purinoceptor activation and cell surface protein ribosylation.




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