Compartmentalized autocrine signaling to cystic fibrosis transmembrane conductance regulator at the apical membrane of airway epithelial cells.
Physical stimulation of airway surfaces evokes liquid secretion, but the events that mediate this vital protective function are not understood. When cystic fibrosis transmembrane conductance regulator (CFTR) channel activity was used as a functional readout, we found signaling elements compartmentalized at both extracellular and intracellular surfaces of the apical cell membrane that activate apical Cl(-) conductance in Calu-3 cells. At the outer surface, ATP was released by physical stimuli, locally converted to adenosine, and sensed by A(2B) adenosine receptors. These receptors couple to G proteins, adenylyl cyclase, and protein kinase A, at the intracellular face of the apical membrane to activate colocalized CFTR. Thus, airways have evolved highly efficient mechanisms to "flush" noxious stimuli from airway surfaces by selective activation of apical membrane signal transduction and effector systems.
Huang
P
P
Cystic Fibrosis Research and Treatment Center, University of North Carolina, Chapel Hill, NC 27599-7248, USA. huangp@med.unc.edu
Lazarowski
E R
ER
Tarran
R
R
Milgram
S L
SL
Boucher
R C
RC
Stutts
M J
MJ
D000241:Adenosine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000378:metabolism; D019898:Autocrine Communication / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004594:Electrophysiology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000166:cytology; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1 / Q000378:metabolism*
C505032:CFTR protein, human; D002712:Chlorides; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D000241:Adenosine