Published ahead of print on January 6, 2006, doi:10.1165/rcmb.2005-0421OC Am. J. Respir. Cell Mol. Biol., Volume 34, Number 5, May 2006, 600-608 A more recent version of this article appeared on May 1, 2006
Submitted on November 9, 2005 Adenosine Regulation of CFTR through Prostenoids in Airway EpitheliaYao Li1,1 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; University of Alabama at Birmingham, Gregory Fleming James Cystic Fibrosis Research Center, Birmingham, AL, USA, 2 Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA; University of Alabama at Birmingham, Gregory Fleming James Cystic Fibrosis Research Center, Birmingham, AL, USA, 3 Southern Research Institute, Birmingham, AL, USA; University of Alabama at Birmingham, Gregory Fleming James Cystic Fibrosis Research Center, Birmingham, AL, USA * To whom correspondence should be addressed. E-mail: jpclancy{at}peds.uab.edu.
Cystic fibrosis is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, leading to altered ion transport, chronic infection, and excessive inflammation. Here we investigated regulation of CFTR in airway cell monolayers by adenosine, adenosine receptors, and arachidonic acid. Our studies demonstrate that the A2B adenosine receptor is expressed at high levels relative to the other adenosine receptor subtypes, with a characteristic low affinity profile for adenosinestimulated CFTR Cl- currents in both Calu-3 cells and CFBE41o- airway cell monolayers stably transduced with wildtype CFTR. The levels of adenosine found in sputum from CF patients with moderate to severe lung disease stimulated apical prostaglandin release in Calu-3 and CFBE41o- cells, implicating adenosine regulation of phospholipase A2 (PLA2) activity. A2B adenosine receptor and arachidonic acid stimulation produced CFTR-dependent currents in airway monolayers and increased cAMP levels that were sensitive to cyclo-oxygenase inhibition. Arachidonic acid demonstrated dual regulation of CFTR, stimulating CFTR and Cl- currents in intact airway monolayers, and potently inhibiting PKA-activated Cl- currents in excised membrane patches. Cl- currents produced by arachidonic acid were sensitive to inhibition of PKA, cyclo-oxygenase, and 5-lipoxygenase. Together, the results provide a converging mechanism to link regulation of CFTR and airway cell inflammation through adenosine and adenosine receptors.
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