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J. Cell Sci. 119 (7): 1320-1328

Research Article

Apical localization of ITPK1 enhances its ability to be a modifier gene product in a murine tracheal cell model of cystic fibrosis

Ling Yang1,2, Jeff Reece2, Sherif E. Gabriel3, and Stephen B. Shears1,2,*

1 Inositol Signaling Section, and N.I.E.H.S. / N.I.H. / D.H.S.S., Research Triangle Park, NC 27709, USA
2 Laboratory of Signal Transduction, N.I.E.H.S. / N.I.H. / D.H.S.S., Research Triangle Park, NC 27709, USA
3 Department of Pediatrics and Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

* Author for correspondence (email: shears{at}

Accepted for publication 14 December 2005.

Abstract: A new aspect of research into the pathogenesis of cystic fibrosis (CF) is a genetics-based search for `modifier genes' that may affect the severity of CF lung disease. Using an alternative, cell biological approach, we show that ITPK1 should be considered a modifier gene. ITPK1 synthesizes an intracellular signal, inositol (3,4,5,6)-tetrakisphosphate [Ins(3,4,5,6)P4]. A bio-activatable, cell-permeable analogue of Ins(3,4,5,6)P4 inhibited Ca2+-dependent secretion of Cl- from polarized monolayers of immortalized mouse tracheal epithelial cells (MTEs). Analysis by high-pressure liquid chromatography showed endogenous Ins(3,4,5,6)P4 levels in CF MTEs were approximately 60% below those in wild-type MTEs (P<0.03). This adaptation, which improves purinergic activation of Ca2+-dependent Cl- secretion in CF MTEs, was exceptionally specific; there was no effect upon the cellular levels of all the other inositol phosphate signals. Real-time PCR provided the explanation: the level of ITPK1 expression in wild-type MTEs was twice as high as that in CF MTEs (P<0.002). The biological impact of this differential gene expression is amplified by ITPK1 being concentrated at the apical membrane of MTEs, which we discovered following confocal immunofluorescence microscopy. Compartmentalization of Ins(3,4,5,6)P4 synthesis adjacent to its site of action will enhance its regulatory capacity.

Key Words: ITPK1 • Cystic fibrosis • inositol phosphates • CFTR • Secretion • Chloride channel

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