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J. Biol. Chem., Vol. 281, Issue 14, 9190-9199, April 7, 2006

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Mechanisms of Cystic Fibrosis Transmembrane Conductance Regulator Activation by S-Nitrosoglutathione^*

Lan Chen, Rakesh P. Patel, Xinjun Teng, Charles A. Bosworth^¶, Jack R. Lancaster, Jr.^¶, and Sadis Matalon^¶1

From the Departments of Anesthesiology, Pathology, and ^¶Physiology and Biophysics, University of Alabama, Birmingham, Alabama 35233

We investigated the mechanisms by which S-nitrosoglutathione (GSNO) alters cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride (Cl^–) secretion across Calu-3 cells, an extensively used model of human airway gland serous cells. Confluent monolayers of Calu-3 cells, grown under an air-liquid interface, were mounted in Ussing chambers for the measurements of chloride short circuit current (I_sc) and trans-epithelial resistance (R_t). Addition of GSNO into the apical compartment of these chambers resulted in significant and sustained increase of I_sc with an IC₅₀ of 3.2 ± 1 µM (mean ± 1 S.E.; n = 6). Addition of either glibenclamide or pre-treatment of Calu-3 cells with the soluble guanylate cyclase inhibitor 1H-(1,2,4)-oxadiazolo[4,3-a]quinoxalin-1-one totally prevented the GSNO-induced increase of I_sc. Conversely, BAY 41-2272, a sGC stimulator, increased I_sc in a dose-response fashion. The GSNO increase of I_sc was reversed by addition of two phosphatases (PP2A1, PP2A2) into the apical compartment of Ussing chambers containing Calu-3 monolayers. Oxy-myoglobin (oxy-Mb, 300 µM) added into the apical compartment of Ussing chambers either prior or after GSNO either completely prevented or immediately reversed the increase of I_sc. However, smaller concentrations of oxy-Mb (1–10 µM), sufficient to scavenge NO in the medium (as assessed by direct measurement of NO in the Ussing chamber using an ISO-NO meter) decreased I_sc partially. Oxy-Mb did not reverse the increase of I_sc following addition of GSNO and cysteine (50 µM). These findings indicate that GSNO stimulates Cl secretion via both cGMP-dependent and cGMP-independent mechanisms.

Received for publication, December 12, 2005 , and in revised form, January 13, 2006.

^* This work was supported by National Institutes of Health Grants HL075540, HL31197, and HL51173 (to S. M.), HL70146 (to R. P.), and HL71189 and HL074391 (to J. R. L.). 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.

¹ To whom correspondence should be addressed: Dept. of Anesthesiology, University of Alabama at Birmingham, 901 19th St. S, BMR II, Rm. 224, Birmingham, AL 35205-3703. Tel.: 205-934-4231; Fax: 205-934-7437; E-mail: sadis{at}uab.edu.

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