title: The cystic fibrosis transmembrane conductance regulator is a dual ATP and chloride channel.
abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to a superfamily of proteins implicated in the transport of ions, proteins, and hydrophobic substances. Recent studies have demonstrated that CFTR is a protein kinase A-sensitive anion channel regulated by ATP. In the present study, patch-clamp techniques were used to assess the role of CFTR in the transport of Cl- and ATP. The stable transfection of mouse mammary carcinoma cells, C127i, with the cDNA for human CFTR resulted in the appearance of a diphenylamine-2-carboxylate-inhibitable Cl- channel, which was activated by cAMP under whole-cell and cell-attached conditions and by protein kinase A plus ATP under excised, inside-out conditions. CFTR expression was also associated with the electrodiffusional movement of ATP as indicated by the cAMP activation of ATP currents measured under whole-cell conditions. In excised, inside-out patches, it was demonstrated that ATP currents were mediated by ATP-conductive channels, which were also activated by protein kinase A and blocked by the Cl- channel blocker diphenylamine-2-carboxylate under excised, inside-out conditions. Single-channel currents observed in the presence of asymmetrical Cl-/ATP concentrations indicated that the same conductive pathway was responsible for both ATP and Cl- movement. Thus, CFTR is a multifunctional protein with more than one anion transport capability and may modify signal transduction pathways for Cl- or other secretory processes by the selective delivery of nucleotides to the extracellular domain.
authors.affiliation: Renal Unit, Massachusetts General Hospital, Boston 02129.
authors.forename: I L
authors.initials: IL
authors.lastname: Reisin
authors.forename: A G
authors.initials: AG
authors.lastname: Prat
authors.forename: E H
authors.initials: EH
authors.lastname: Abraham
authors.forename: J F
authors.initials: JF
authors.lastname: Amara
authors.forename: R J
authors.initials: RJ
authors.lastname: Gregory
authors.forename: D A
authors.initials: DA
authors.lastname: Ausiello
authors.forename: H F
authors.initials: HF
authors.lastname: Cantiello
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D006801:Humans; D017136:Ion Transport; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D014162:Transfection; D014407:Tumor Cells, Cultured; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: C505032:CFTR protein, human; D018118:Chloride Channels; D008565:Membrane Proteins; D062367:ortho-Aminobenzoates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate; C001209:fenamic acid; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid