Cell to cell communication in response to mechanical stress via bilateral release of ATP and UTP in polarized epithelia.
Airway epithelia are positioned at the interface between the body and the environment, and generate complex signaling responses to inhaled toxins and other stresses. Luminal mechanical stimulation of airway epithelial cells produces a propagating wave of elevated intracellular Ca(2+) that coordinates components of the integrated epithelial stress response. In polarized airway epithelia, this response has been attributed to IP(3) permeation through gap junctions. Using a combination of approaches, including enzymes that destroy extracellular nucleotides, purinergic receptor desensitization, and airway cells deficient in purinoceptors, we demonstrated that Ca(2+) waves induced by luminal mechanical stimulation in polarized airway epithelia were initiated by the release of the 5' nucleotides, ATP and UTP, across both apical and basolateral membranes. The nucleotides released into the extracellular compartment interacted with purinoceptors at both membranes to trigger Ca(2+) mobilization. Physiologically, apical membrane nucleotide-release coordinates airway mucociliary clearance responses (mucin and salt, water secretion, increased ciliary beat frequency), whereas basolateral release constitutes a paracrine mechanism by which mechanical stresses signal adjacent cells not only within the epithelium, but other cell types (nerves, inflammatory cells) in the submucosa. Nucleotide-release ipsilateral and contralateral to the surface stimulated constitutes a unique mechanism by which epithelia coordinate local and distant airway defense responses to mechanical stimuli.
Homolya
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Cystic Fibrosis Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Steinberg
T H
TH
Boucher
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RC
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001980:Bronchi / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D051379:Mice; D018345:Mice, Knockout; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D013314:Stress, Mechanical; D014544:Uridine Triphosphate / Q000378:metabolism*
C546385:P2RY2 protein, human; C546386:P2ry2 protein, mouse; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D000255:Adenosine Triphosphate; D001081:Apyrase; D002118:Calcium; D014544:Uridine Triphosphate