Purinergic signaling underlies CFTR control of human airway epithelial cell volume

Gavin M. Braunstein, A. Zsembery, Torry A. Tucker, Erik M. Schwiebert

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function in cystic fibrosis (CF) causes dysregulation of multiple ion channels, water channels, and acid-base transporters in epithelia. As such, we hypothesized that dysregulation of many critical ion channels and transporters may cause defects in human airway epithelial cell volume regulation. Methods: Cell volume, regulatory volume decrease, and its regulation was assessed in real-time via Coulter Counter Multisizer III-driven electronic cell sizing in non-CF, CF, and CFTR-complemented CF human airway epithelial cells. SPQ halide fluorescence assay of hypotonicity-induced chloride efflux provided indirect validation of the cell volume assays. Results: CFTR, via autocrine ATP signaling, governs human airway epithelial cell volume regulation. Non-CF cells and wild-type (WT)-CFTR-transfected CF cells had normal regulatory volume decrease (RVD) responses that were attenuated by blockade of autocrine and paracrine purinergic signaling. In contrast, parental IB3-1 CF cells or IB3-1 cells expressing CFTR mutants (ΔF508, G551D, and S1455X) failed to RVD. CF cell RVD was rescued by agonists to P2Y G protein-coupled receptors and, more robustly, by agonists to P2X purinergic receptor channels. Conclusions: Loss of CFTR and CFTR-driven autocrine ATP signaling may underlie defective cell volume regulation and dysregulated ion, water, and acid-base transport in CF airway epithelia.

Original languageEnglish
Pages (from-to)99-117
Number of pages19
JournalJournal of Cystic Fibrosis
Volume3
Issue number2
DOIs
Publication statusPublished - Jun 2004

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Cystic Fibrosis Transmembrane Conductance Regulator
Airway Management
Cell Size
Cystic Fibrosis
Epithelial Cells
Autocrine Communication
Ion Channels
Purinergic P2X Receptor Agonists
Fibrosis
Epithelium
Adenosine Triphosphate
Paracrine Communication
Aquaporins
Acids
G-Protein-Coupled Receptors
Chlorides
Fluorescence
Ions
Water

Keywords

  • Calcium entry channels
  • Cystic fibrosis
  • P2X receptors
  • P2Y receptors
  • Regulatory volume decrease

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Purinergic signaling underlies CFTR control of human airway epithelial cell volume. / Braunstein, Gavin M.; Zsembery, A.; Tucker, Torry A.; Schwiebert, Erik M.

In: Journal of Cystic Fibrosis, Vol. 3, No. 2, 06.2004, p. 99-117.

Research output: Contribution to journalArticle

Braunstein, Gavin M. ; Zsembery, A. ; Tucker, Torry A. ; Schwiebert, Erik M. / Purinergic signaling underlies CFTR control of human airway epithelial cell volume. In: Journal of Cystic Fibrosis. 2004 ; Vol. 3, No. 2. pp. 99-117.
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N2 - Background: Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function in cystic fibrosis (CF) causes dysregulation of multiple ion channels, water channels, and acid-base transporters in epithelia. As such, we hypothesized that dysregulation of many critical ion channels and transporters may cause defects in human airway epithelial cell volume regulation. Methods: Cell volume, regulatory volume decrease, and its regulation was assessed in real-time via Coulter Counter Multisizer III-driven electronic cell sizing in non-CF, CF, and CFTR-complemented CF human airway epithelial cells. SPQ halide fluorescence assay of hypotonicity-induced chloride efflux provided indirect validation of the cell volume assays. Results: CFTR, via autocrine ATP signaling, governs human airway epithelial cell volume regulation. Non-CF cells and wild-type (WT)-CFTR-transfected CF cells had normal regulatory volume decrease (RVD) responses that were attenuated by blockade of autocrine and paracrine purinergic signaling. In contrast, parental IB3-1 CF cells or IB3-1 cells expressing CFTR mutants (ΔF508, G551D, and S1455X) failed to RVD. CF cell RVD was rescued by agonists to P2Y G protein-coupled receptors and, more robustly, by agonists to P2X purinergic receptor channels. Conclusions: Loss of CFTR and CFTR-driven autocrine ATP signaling may underlie defective cell volume regulation and dysregulated ion, water, and acid-base transport in CF airway epithelia.

AB - Background: Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function in cystic fibrosis (CF) causes dysregulation of multiple ion channels, water channels, and acid-base transporters in epithelia. As such, we hypothesized that dysregulation of many critical ion channels and transporters may cause defects in human airway epithelial cell volume regulation. Methods: Cell volume, regulatory volume decrease, and its regulation was assessed in real-time via Coulter Counter Multisizer III-driven electronic cell sizing in non-CF, CF, and CFTR-complemented CF human airway epithelial cells. SPQ halide fluorescence assay of hypotonicity-induced chloride efflux provided indirect validation of the cell volume assays. Results: CFTR, via autocrine ATP signaling, governs human airway epithelial cell volume regulation. Non-CF cells and wild-type (WT)-CFTR-transfected CF cells had normal regulatory volume decrease (RVD) responses that were attenuated by blockade of autocrine and paracrine purinergic signaling. In contrast, parental IB3-1 CF cells or IB3-1 cells expressing CFTR mutants (ΔF508, G551D, and S1455X) failed to RVD. CF cell RVD was rescued by agonists to P2Y G protein-coupled receptors and, more robustly, by agonists to P2X purinergic receptor channels. Conclusions: Loss of CFTR and CFTR-driven autocrine ATP signaling may underlie defective cell volume regulation and dysregulated ion, water, and acid-base transport in CF airway epithelia.

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