Compartmentalized autocrine signaling to cystic fibrosis transmembrane conductance regulator at the apical membrane of airway epithelial cells
- Pingbo Huang*,†,
- Eduardo R. Lazarowski*,
- Robert Tarran*,
- Sharon L. Milgram‡,
- Richard C. Boucher*, and
- M. Jackson Stutts*
- *Cystic Fibrosis Research and Treatment Center, and ‡Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, NC 27599-7248
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Edited by Peter C. Agre, Johns Hopkins University School of Medicine, Baltimore, MD, and approved September 18, 2001 (received for review June 25, 2001)
Abstract
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 A2B 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.
Footnotes
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↵ † To whom reprint requests should be addressed. E-mail: huangp{at}med.unc.edu.
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This paper was submitted directly (Track II) to the PNAS office.
- Abbreviations:
- CFTR,
- cystic fibrosis transmembrane conductance regulator;
- AC,
- adenylyl cyclase;
- Ado,
- adenosine;
- AMPCP,
- adenosine 5′-[α,β-methylene]diphosphate;
- GDPβS,
- guanosine 5′-[β-thio]diphosphate;
- GTPγS,
- guanosine 5′-[γ-thio]triphosphate;
- 8-SPT,
- 8-(p-sulfophenyl)theophylline;
- PKA,
- protein kinase A;
- PKI,
- PKA inhibitor;
- A2BAR,
- A2B adenosine receptors
- Copyright © 2001, The National Academy of Sciences
