CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP.
The cystic fibrosis transmembrane conductance regulator (CFTR) functions to regulate both Cl- and Na+ conductive pathways; however, the cellular mechanisms whereby CFTR acts as a conductance regulator are unknown. CFTR and outwardly rectifying Cl- channels (ORCCs) are distinct channels but are linked functionally via an unknown regulatory mechanism. We present results from whole-cell and single-channel patch-clamp recordings, short-circuit current recordings, and [gamma-32P]ATP release assays of normal, CF, and wild-type or mutant CFTR-transfected CF airway cultured epithelial cells wherein CFTR regulates ORCCs by triggering the transport of the potent agonist, ATP, out of the cell. Once released, ATP stimulates ORCCs through a P2U purinergic receptor-dependent signaling mechanism. Our results suggest that CFTR functions to regulate other Cl- secretory pathways in addition to itself conducting Cl-.
Schwiebert
E M
EM
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Egan
M E
ME
Hwang
T H
TH
Fulmer
S B
SB
Allen
S S
SS
Cutting
G R
GR
Guggino
W B
WB
D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D008961:Models, Structural; D018408:Patch-Clamp Techniques; D011994:Recombinant Proteins / Q000378:metabolism; D014132:Trachea / Q000502:physiology* / Q000503:physiopathology; D014162:Transfection
C505032:CFTR protein, human; D018118:Chloride Channels; D008565:Membrane Proteins; D011994:Recombinant Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate; D000242:Cyclic AMP