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First published online March 22, 2006

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Signalling cystic fibrosis severity

Cystic fibrosis (CF), which affects the lungs and epithelia from other tissues, is caused by mutations in the cyclic-AMP-activated Cl^- channel CFTR. The severity of the disease, however, varies widely between patients with the same CFTR mutation and must therefore be influenced by additional factors. On p. 1320, Stephen Shears and colleagues identify ITPK1, a kinase that produces the signalling molecule inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P₄], as a potential modifier. Using an airway-epithelial-cell model, the authors show that Ins(3,4,5,6)P₄ inhibits Ca²⁺-dependent Cl^- secretion - this is upregulated in CF and partly compensates for the CFTR defect. They also show that Ins(3,4,5,6)P₄ levels are reduced in murine tracheal CF epithelial (MTE) cells because of reduced expression of ITPK1. Furthermore, they note that ITPK1 is localized at the apical membrane of MTE cells, close to the Ca²⁺-dependent Cl^- channels that its product inhibits. The authors suggest, therefore, that variability in ITPK1 expression may contribute to CF severity by affecting how well the Ca²⁺-dependent Cl^- channels compensate for loss of CFTR.

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Related articles in JCS:

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

Ling Yang, Jeff Reece, Sherif E. Gabriel, and Stephen B. Shears
JCS 2006 119: 1320-1328. [Abstract] [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Social Bookmarking                         What's this?