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Activation of Airway Cl^– Secretion in Human Subjects by Adenosine

Departments of Pediatrics and Medicine, the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama; and Department of Human Genetics, Georgetown University, Washington, DC

Address correspondence to: J. P. Clancy, M.D., Department of Pediatrics, 620 ACC, 1600 7th Avenue South, Birmingham, AL 35233. E-mail: jclancy{at}peds.uab.edu

We investigated cystic fibrosis (CF) transmembrane conductance regulator (CFTR) regulation by A₂ adenosine (Ado) receptors and ß₂ adrenergic receptors in CFTR-corrected CFBE41o- airway cells and human subjects. CFBE41o- cells stimulated with Ado (10 µM), isoproterenol (Iso, 10 µM), or Ado + Iso (10 µM each) elevated cyclic AMP (cAMP) above control conditions (P < 0.001), with the Iso conditions increasing cAMP 10-fold above that produced by Ado alone (P < 0.001). All agonist conditions had similar effects on short circuit current at 10 and 25 µM, with no further currents produced by subsequent stimulation with forskolin (20 µM). CFTR dependence was demonstrated by glybenclamide block of agonist-stimulated currents. Nasal potential difference studies in normal (n = 50) subjects demonstrated that Ado (10 µM) and Ado + Iso (10 µM each) produced more polarization compared with Iso (10 µM Ado increase = 44%, 10 µM Ado + Iso increase = 52%, P < 0.05 for each condition compared with Iso alone). Studies completed in patients with CF (n = 10, "severe" genotypes) confirmed that Ado-stimulated polarization was CFTR-dependent. Together, these results indicate that Ado is a potent Cl^– secretagogue in vivo, with relatively small effects on cAMP levels despite strong effects on CFTR-dependent short circuit current and nasal Cl^– transport. These findings support growing evidence indicating a role for Ado regulation of CFTR-dependent Cl^– secretion in vivo.

Abbreviations: ß₂ adrenergic receptor, ß₂ AR • A_2B adenosine receptor, A_2B AR • African American, AA • adenosine, Ado • A kinase anchoring proteins, AKAPs • cyclic AMP, cAMP • cystic fibrosis, CF • CF transmembrane conductance regulator, CFTR • G protein coupled receptor, GPCR • short circuit current, I_sc • isoproterenol, Iso • potential difference, P.D. • protein kinase, PK

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