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Am J Physiol. 1999 Feb;276(2):C361-9. doi: 10.1152/ajpcell.1999.276.2.C361.

Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway.

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Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005, USA.


ATP and its metabolites stimulate Cl- secretion in human epithelium in vitro and in vivo. The specific purinergic receptor subtypes that govern these effects have been difficult to separate, in part due to multiple parallel pathways for Cl- secretion in respiratory and intestinal epithelia. In a simplified model using COS-7 cells, we demonstrate acquisition of an ATP-, ADP-, AMP-, and adenosine (ADO)-regulated halide permeability specifically following expression of wild-type (wt) cystic fibrosis transmembrane conductance regulator (CFTR). This halide permeability is blocked by the P1 purinergic receptor antagonist 8-phenyl theophylline, sensitive to the protein kinase A inhibitor H-89, and associated with a modest, dose-dependent increase in cellular cAMP concentration. Phorbol esters poorly activate halide permeability compared with ADO, and ADO-stimulated efflux was not affected by treatment with the protein kinase C inhibitor bisindolylmaleimide I. The A2 ADO receptor (AR) agonists 5'-N-ethylcarboxamide adenosine and ADO were strong activators, whereas the A1 AR agonist R-phenylisopropyladenosine failed to activate halide permeability. Metabolic conversion of ADO nucleotides by surface ecto-5'-nucleotidase to more active (less phosphorylated) forms contributes to anion transport activation in these cells. Immunoprecipitation with anti-A2B AR antibody identified a 31-kDa protein in both COS-7 and human bronchial epithelial cells. Together, these findings indicate that ADO and its nucleotides are capable of activating wtCFTR-dependent halide permeability through A2B AR and that this AR subtype is present in human bronchial epithelium. We also present data showing that this pathway can activate clinically significant mutant CFTR molecules such as R117H.

[Indexed for MEDLINE]

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