Model of ion transport regulation in chloride-secreting airway epithelial cells. Integrated description of electrical, chemical, and fluorescence measurements.
An electrokinetic model was developed to calculate the time course of electrical parameters, ion fluxes, and intracellular ion activities for experiments performed in airway epithelial cells. Model variables included cell [Na], [K], [Cl], volume, and membrane potentials. The model contained apical membrane Cl, Na, and K conductances, basolateral membrane K conductance, Na/K/2 Cl and Na/Cl symport, and 3 Na/2 K ATPase, and a paracellular conductance. Transporter permeabilities and ion saturabilities were determined from reported ion flux data and membrane potentials in intact canine trachea. Without additional assumptions, the model predicted accurately the measured short-circuit current (Isc), cellular conductances, voltage-divider ratios, open-circuit potentials, and the time course of cell ion composition in ion substitution experiments. The model was used to examine quantitatively: (a) the effect of transport inhibitors on Isc and membrane potentials, (b) the dual role of apical Cl and basolateral K conductance in cell secretion, (c) whether the basolateral symporter requires K, and (d) the regulation of apical Cl conductance by cAMP and Ca-dependent signaling pathways. Model predictions gave improved understanding of the interrelations among transporting systems and in many cases gave surprising predictions that were not obvious without a detailed model. The model developed here has direct application to secretory or absorptive epithelial cells in the kidney thick ascending limb, cornea, sweat duct, and intestine in normal and pathophysiological states such as cystic fibrosis and cholera.
Department of Medicine, University of California, San Francisco 94143.
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Hartmann
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Verkman
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D018118:Chloride Channels; D003198:Computer Simulation; D000242:Cyclic AMP / Q000494:pharmacology; D004285:Dogs; D004848:Epithelium / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D008433:Mathematics; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000502:physiology*; D008954:Models, Biological; D009130:Muscle, Smooth / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014132:Trachea / Q000502:physiology
D018118:Chloride Channels; D007473:Ion Channels; D008565:Membrane Proteins; D015221:Potassium Channels; D000242:Cyclic AMP; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium