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J. Biol. Chem., Vol. 279, Issue 11, 10720-10729, March 12, 2004

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Extracellular Zinc and ATP Restore Chloride Secretion across Cystic Fibrosis Airway Epithelia by Triggering Calcium Entry^*

Ákos Zsembery¶||, James A. Fortenberry, Lihua Liang, Zsuzsa Bebok**, Torry A. Tucker, Amanda T. Boyce**, Gavin M. Braunstein, Elisabeth Welty, P. Darwin Bell, Eric J. Sorscher, J. P. Clancy, and Erik M. Schwiebert**

From the Departments of Physiology and Biophysics, ^**Cell Biology, and Medicine and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, Birmingham, Alabama, 35294-0005 and the ^¶Hungarian Academy of Science and Semmelweis University Nephrology Research Group, 1089 Nagyvárad tér 4, Budapest H-1089, Hungary

Cystic fibrosis (CF) is caused by defective cyclic AMP-dependent cystic fibrosis transmembrane conductance regulator Cl^- channels. Thus, CF epithelia fail to transport Cl^- and water. A postulated therapeutic avenue in CF is activation of alternative Ca²⁺-dependent Cl^- channels. We hypothesized that stimulation of Ca²⁺ entry from the extracellular space could trigger a sustained Ca²⁺ signal to activate Ca²⁺-dependent Cl^- channels. Cytosolic [Ca²⁺]_i was measured in non-polarized human CF (IB3-1) and non-CF (16HBE14o^-) airway epithelial cells. Primary human CF and non-CF airway epithelial monolayers as well as Calu-3 monolayers were used to assess anion secretion. In vivo nasal potential difference measurements were performed in non-CF and two different CF mouse (F508 homozygous and bitransgenic gut-corrected but lung-null) models. Zinc and ATP induced a sustained, reversible, and reproducible increase in cytosolic Ca²⁺ in CF and non-CF cells with chemistry and pharmacology most consistent with activation of P2X purinergic receptor channels. P2X purinergic receptor channel-mediated Ca²⁺ entry stimulated sustained Cl^- and secretion in CF and non-CF epithelial monolayers. In non-CF mice, zinc and ATP induced a significant Cl^- secretory response similar to the effects of agonists that increase intracellular cAMP levels. More importantly, in both CF mouse models, Cl^- permeability of nasal epithelia was restored in a sustained manner by zinc and ATP. These effects were reversible and reacquirable upon removal and readdition of agonists. Our data suggest that activation of P2X calcium entry channels may have profound therapeutic benefit for CF that is independent of cystic fibrosis transmembrane conductance regulator genotype.

Received for publication, December 8, 2003 , and in revised form, December 22, 2003.

^* This work was supported by National Institutes of Health R01 Grants HL 63934 and DK 54367 (to E. M. S.) and by the Hungarian Scientific Research Fund (OTKA) Grant T037524 (to A. Z.). Two provisional patents have been filed and established (Serial Nos. 60/441,045 and 60/475,423) with the United States Patent and Trademark Office to claim our findings. A full utility patent application will be filed in January 2004. No licensing agreements have been established to date. A dialogue has begun with the Cystic Fibrosis Foundation Therapeutics, Inc. and the Cystic Fibrosis Foundation Therapeutic Development Network with regard to beginning "proof of concept" clinical trials for cystic fibrosis with zinc-based formulations. 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.

|| Co-director of the Cystic Fibrosis Center's Electrophysiology Assay CORE within a Specialized Center of Research (SCOR) grant (with logistical support from National Institutes of Health Grant DK 62397). To whom correspondence may be addressed: Dept. of Physiology and Biophysics, University of Alabama, MCLM 740, 1918 University Blvd., Birmingham, AL 35294-0005. Tel.: 205-934-6235; Fax: 205-934-1445; E-mail: zsembery{at}physiology.uab.edu. Director of the Cystic Fibrosis Center's Electrophysiology Assay CORE within a Specialized Center of Research (SCOR) grant (with logistical support from National Institutes of Health Grant DK 62397). To whom correspondence may be addressed: Dept. of Physiology and Biophysics, University of Alabama, MCLM 740, 1918 University Blvd., Birmingham, AL 35294-0005. Tel.: 205-934-6234; Fax: 205-934-1445; E-mail: eschwiebert{at}physiology.uab.edu.

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