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Protein phosphatase 1 coordinates CFTR-dependent airway epithelial HCO3- secretion by reciprocal regulation of apical and basolateral membrane Cl--HCO3- exchangers

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


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Background and Purpose Our recent studies on human airway serous-like Calu-3 cells showed that cAMP agonists stimulated a HCO3 rich secretion containing up to 80mM HCO3. This alkaline secretion relied on a coordinated switch in the activity of distinct Cl-HCO3 anion exchangers (AE) located at different regions of the cell. At the apical membrane, cAMP agonists activated the electroneutral AE pendrin (SLC26A4), together with cystic fibrosis transmembrane conductance regulator (CFTR), while at the basolateral membrane the agonists inhibited AE2 (SLC4A2). However, the underlying mechanism(s) that orchestrates this cAMP-dependent switch in AE activity has not been elucidated. Experimental Approach Apical and basolateral Cl-HCO3 exchange was assessed by measuring Cl-dependent changes in intracellular pH (pHi). Key Results We show that protein phosphatase 1 (PP1), together with CFTR, play central roles in this reciprocal regulation of AE activity. Activation of pendrin by cAMP agonists, but not inhibition of the basolateral exchanger, was protein kinase A-dependent. Knocking down CFTR expression, or blocking its activity with GlyH-101, led to incomplete inhibition of the basolateral AE by cAMP, supporting a role for CFTR in this process. Addition of the PP1/2A inhibitor, okadaic acid, but not the PP2A specific inhibitor fostreicin, mimicked the effect of cAMP stimulation. Furthermore, okadaic acid-treated Calu-3 monolayers produced a more alkaline fluid than untreated cells, which was comparable with that produced by cAMP stimulation. Conclusions and Implications These results identify PP1 as a novel regulator of AE activity which, in concert with CFTR, coordinates events at both apical and basolateral membranes, crucial for efficient HCO3 secretion from Calu-3 cells.

Publication metadata

Author(s): Garnett JP, Hickman E, Tunkamnerdthai O, Cuthbert AW, Gray MA

Publication type: Article

Publication status: Published

Journal: British Journal of Pharmacology

Year: 2013

Volume: 168

Issue: 8

Pages: 1946-1960

Print publication date: 25/03/2013

ISSN (print): 0007-1188

ISSN (electronic): 1365-2125

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1111/bph.12085


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