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J. Biol. Chem., Vol. 280, Issue 11, 10202-10209, March 18, 2005

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Cystic Fibrosis Airway Epithelial Ca²⁺_i Signaling

THE MECHANISM FOR THE LARGER AGONIST-MEDIATED Ca²⁺_i SIGNALS IN HUMAN CYSTIC FIBROSIS AIRWAY EPITHELIA^*

Carla M. Pedrosa Ribeiro, Anthony M. Paradiso, Mark A. Carew¶, Stephen B. Shears¶, and Richard C. Boucher

From the Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, North Carolina 27599-7248 and ^¶Inositide Signaling Section, Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

In cystic fibrosis (CF) airways, abnormal epithelial ion transport likely initiates mucus stasis, resulting in persistent airway infections and chronic inflammation. Mucus clearance is regulated, in part, by activation of apical membrane receptors coupled to intracellular calcium (Ca²⁺_i) mobilization. We have shown that Ca²⁺_i signals resulting from apical purinoceptor (P2Y₂-R) activation are increased in CF compared with normal human airway epithelia. The present study addressed the mechanism for the larger apical P2Y₂-R-dependent Ca²⁺_i signals in CF human airway epithelia. We show that the increased Ca²⁺_i mobilization in CF was not specific to P2Y₂-Rs because it was mimicked by apical bradykinin receptor activation, and it did not result from a greater number of P2Y₂-R or a more efficient coupling between P2Y₂-Rs and phospholipase C-generated inositol 1,4,5-trisphosphate. Rather, the larger apical P2Y₂-R activation-promoted Ca²⁺_i signals in CF epithelia resulted from an increased density and Ca²⁺ storage capacity of apically confined endoplasmic reticulum (ER) Ca²⁺ stores. To address whether the ER up-regulation resulted from ER retention of misfolded F508 CFTR or was an acquired response to chronic luminal airway infection/inflammation, three approaches were used. First, ER density was studied in normal and CF sweat duct human epithelia expressing high levels of F508 CFTR, and it was found to be the same in normal and CF epithelia. Second, apical ER density was morphometrically analyzed in airway epithelia from normal subjects, F508 homozygous CF patients, and a disease control, primary ciliary dyskinesia; it was found to be greater in both CF and primary ciliary dyskinesia. Third, apical ER density and P2Y₂-R activation-mobilized Ca²⁺_i, which were investigated in airway epithelia in a long term culture in the absence of luminal infection, were similar in normal and CF epithelia. To directly test whether luminal infection/inflammation triggers an up-regulation of the apically confined ER Ca²⁺ stores, normal airway epithelia were chronically exposed to supernatant from mucopurulent material from CF airways. Supernatant treatment expanded the apically confined ER, resulting in larger apical P2Y₂-R activation-dependent Ca²⁺_i responses, which reproduced the increased Ca²⁺_i signals observed in CF epithelia. In conclusion, the mechanism for the larger Ca²⁺_i signals elicited by apical P2Y₂-R activation in CF airway epithelia is an expansion of the apical ER Ca²⁺ stores triggered by chronic luminal airway infection/inflammation. Greater ER-derived Ca²⁺_i signals may provide a compensatory mechanism to restore, at least acutely, mucus clearance in CF airways.

Received for publication, September 15, 2004 , and in revised form, January 6, 2005.

^* This work was supported in part by Cystic Fibrosis Foundation Grants CFF RIBEIR00Z0 and CFF RIBEIR00G0 (to C. M. P. R.) and by National Institutes of Health Grants HL34322 and HL60280 (to R. C. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 919-966-7045; Fax: 919-966-5178; E-mail: carla_ribeiro{at}med.unc.edu.

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