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Lookup NU author(s): Salam Ibrahim, Mark Turner, Dr Vinciane Saint-CriqORCiD, Dr James Garnett, Dr Iram Haq, Dr Malcolm Brodlie, Professor Christopher WardORCiD, Dr Michael Gray
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Transepithelial bicarbonate secretion by human airway submucosal glands and surface epithelial cells is crucial to maintain the pH-sensitive innate defence mechanisms of the lung. cAMP agonists stimulate HCO3- secretion via coordinated increases in basolateral HCO3- influx and accumulation, as well as CFTR-dependent HCO3- efflux at the luminal membrane of airway epithelial cells. Here, we investigated the regulation of a basolateral located, DIDS-sensitive, Cl-/HCO3- exchanger, anion exchanger 2 (AE2; SLC4A2) which is postulated to act as an acid loader, and therefore potential regulator of HCO3- secretion, in human airway epithelial cells. Using intracellular pH measurements performed on Calu-3 cells, we demonstrate that the activity of the basolateral Cl-/HCO3- exchanger was significantly downregulated by cAMP agonists, via a PKA-independent mechanism and also required Ca2+ and calmodulin under resting conditions. AE2 contains potential phosphorylation sites by a calmodulin substrate, protein kinase CK2, and we demonstrated that AE2 activity was reduced in the presence of CK2 inhibition. Moreover, CK2 inhibition abolished the activity of AE2 in primary human nasal epithelia. Studies performed on mouse AE2 transfected into HEK-293T cells confirmed almost identical Ca2+/calmodulin and CK2 regulation to that observed in Calu-3 and primary human nasal cells. Furthermore, mouse AE2 activity was reduced by genetic knockout of CK2, an effect which was rescued by exogenous CK2 expression. Together, these findings are the first to demonstrate that CK2 is a key regulator of Cl--dependent HCO3- export at the serosal membrane of human airway epithelial cells.
Author(s): Ibrahim SH, Turner MJ, Saint-Criq V, Garnett J, Haq IJ, Brodlie M, Ward C, Borgo C, Salvi M, Venerando A, Gray MA
Publication type: Article
Publication status: Published
Journal: Pflügers Archiv - European Journal of Physiology
Year: 2017
Volume: 469
Issue: 9
Pages: 1073-1091
Print publication date: 01/09/2017
Online publication date: 28/04/2017
Acceptance date: 10/04/2017
Date deposited: 01/06/2017
ISSN (electronic): 1432-2013
Publisher: Springer
URL: http://doi.org/10.1007/s00424-017-1981-3
DOI: 10.1007/s00424-017-1981-3
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