Polarized signaling via purinoceptors in normal and cystic fibrosis airway epithelia.
Airway epithelia are confronted with distinct signals emanating from the luminal and/or serosal environments. This study tested whether airway epithelia exhibit polarized intracellular free calcium (Ca(2+)(i)) and anion secretory responses to 5' triphosphate nucleotides (ATP/UTP), which may be released across both barriers of these epithelia. In both normal and cystic fibrosis (CF) airway epithelia, mucosal exposure to ATP/UTP increased Ca(2+)(i) and anion secretion, but both responses were greater in magnitude for CF epithelia. In CF epithelia, the mucosal nucleotide-induced response was mediated exclusively via Ca(2+)(i) interacting with a Ca(2+)-activated Cl(-) channel (CaCC). In normal airway epithelia (but not CF), nucleotides stimulated a component of anion secretion via a chelerythrine-sensitive, Ca(2+)-independent PKC activation of cystic fibrosis transmembrane conductance regulator. In normal and CF airway epithelia, serosally applied ATP or UTP were equally effective in mobilizing Ca(2+)(i). However, serosally applied nucleotides failed to induce anion transport in CF epithelia, whereas a PKC-regulated anion secretory response was detected in normal airway epithelia. We conclude that (1) in normal nasal epithelium, apical/basolateral purinergic receptor activation by ATP/UTP regulates separate Ca(2+)-sensitive and Ca(2+)-insensitive (PKC-mediated) anion conductances; (2) in CF airway epithelia, the mucosal ATP/UTP-dependent anion secretory response is mediated exclusively via Ca(2+)(i); and (3) Ca(2+)(i) regulation of the Ca(2+)-sensitive anion conductance (via CaCC) is compartmentalized in both CF and normal airway epithelia, with basolaterally released Ca(2+)(i) failing to activate CaCC in both epithelia.
Paradiso
A M
AM
Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. paradiso@med.unc.edu
Ribeiro
C M
CM
Boucher
R C
RC
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D017920:Antiporters / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology; D018929:Cell Culture Techniques; D003550:Cystic Fibrosis / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000494:pharmacology*; D004848:Epithelium / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D011983:Receptors, Purinergic / Q000502:physiology*; D015398:Signal Transduction; D014544:Uridine Triphosphate / Q000494:pharmacology
D017920:Antiporters; C505032:CFTR protein, human; D015220:Calcium Channels; D011983:Receptors, Purinergic; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate; D014544:Uridine Triphosphate