Apical and basolateral ATP stimulates tracheal epithelial chloride secretion via multiple purinergic receptors

Tae Ho Hwang, Erik M. Schwiebert, William B. Guggino

Research output: Contribution to journalArticle

Abstract

Stimulation of Cl- secretion across the airway epithelium by ATP or UTP as agonists has therapeutic implications for cystic fibrosis. Our results demonstrate that ATP stimulates Cl- secretion in rat tracheal epithelial cell monolayers in primary culture from the apical or basolateral side of the monolayer. Multiple types of ATP-sensitive Cl- conductances in intact monolayers were elucidated through inhibition by Cl- channel-blocking drugs. Multiple Cl- conductances stimulated by ATP and adenosine 3',5'-cyclic monophosphate (cAMP) (tested for comparison) were also deciphered more specifically by nystatin permeabilization of the basolateral membrane, subsequent imposition of symmetrical Cl-, I-, or Br- solutions to test halide permselectivity, inhibition by Cl- channel-blocking drugs, and construction of current-voltage plots to study time and voltage dependence of the currents. Apical ATP stimulates Cl- secretion through P(2U) (or P(2Y2)) purinergic receptors via both intracellular Ca(i)/2+ (Ca(i)/2+)-dependent and Ca(i)/2+-independent signaling pathways by opening outwardly rectifying Cl- channels (ORCCs), cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels, and Ca(i)/2+-dependent Cl- channels. Basolateral ATP stimulates Cl- secretion via a combination of receptor subtypes (P(2T) and P(2U)) or a novel type of receptor (P(2Y3)), independent of Ca(i)/2+ or cAMP signaling by opening only CFTR channels. cAMP also stimulated multiple types of Cl- conductances, consistent with simultaneous activation of CFTR and ORCCs. Together, these results suggest that ATP as an agonist stimulates Cl- secretion via multiple purinergic receptors and multiple signal transduction pathways activated in different membrane domains of tracheal epithelia.

Original languageEnglish (US)
Pages (from-to)C1611-C1623
JournalAmerican Journal of Physiology - Cell Physiology
Volume270
Issue number6 39-6
StatePublished - Jun 1 1996

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Keywords

  • Ussing chamber
  • adenosine 3',5'-cyclic monophosphate
  • chloride channels
  • cystic fibrosis
  • intracellular calcium

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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