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Novel Role for Pendrin in Orchestrating Bicarbonate Secretion in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-expressing Airway Serous Cells

Lookup NU author(s): Dr James Garnett, Dr Michael Gray

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Abstract

In most HCO3--secreting epithelial tissues, SLC26 Cl-/HCO3- transporters work in concert with the cystic fibrosis transmembrane conductance regulator (CFTR) to regulate the magnitude and composition of the secreted fluid, a process that is vital for normal tissue function. By contrast, CFTR is regarded as the only exit pathway for HCO3- in the airways. Here we show that Cl-/HCO3- anion exchange makes a major contribution to transcellular HCO3- transport in airway serous cells. Real-time measurement of intracellular pH from polarized cultures of human Calu-3 cells demonstrated cAMP/PKA-activated Cl--dependent HCO3- transport across the luminal membrane via CFTR-dependent coupled Cl-/HCO3- anion exchange. The pharmacological and functional profile of the luminal anion exchanger was consistent with SLC26A4 (pendrin), which was shown to be expressed by quantitative RT-PCR, Western blot, and immunofluorescence. Pendrin-mediated anion exchange activity was confirmed by shRNA pendrin knockdown (KD), which markedly reduced cAMP-activated Cl-/HCO3- exchange. To establish the relative roles of CFTR and pendrin in net HCO3- secretion, transepithelial liquid secretion rate and liquid pH were measured in wild type, pendrin KD, and CFTR KD cells. cAMP/PKA increased the rate and pH of the secreted fluid. Inhibiting CFTR reduced the rate of liquid secretion but not the pH, whereas decreasing pendrin activity lowered pH with little effect on volume. These results establish that CFTR predominately controls the rate of liquid secretion, whereas pendrin regulates the composition of the secreted fluid and identifies a critical role for this anion exchanger in transcellular HCO3- secretion in airway serous cells.

Publication metadata

Author(s): Garnett JP, Hickman E, Burrows R, Hegyi P, Tiszlavicz L, Cuthbert AW, Fong PY, Gray MA

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2011

Volume: 286

Issue: 47

Pages: 41069-41082

Print publication date: 01/11/2011

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.

URL: http://dx.doi.org/10.1074/jbc.M111.266734

DOI: 10.1074/jbc.M111.266734

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