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The present study reports that quercetin (a flavonoid) stimulated bumetanide-sensitive Cl\u2212 secretion with reduction of apical Cl\u2212 conductance, suggesting that quercetin stimulates Cl\u2212 secretion by activating an entry step of Cl\u2212 across the basolateral membrane through Na+\/K+\/2Cl\u2212 cotransporter (NKCC1). To clarify the mechanism stimulating NKCC1 by quercetin, we verified involvement of protein kinase (PK)A, PKC, protein tyrosine kinase (PTK), and cytosolic Ca2+-dependent pathways. A PKA inhibitor (PKI-14\u201322 amide), a PKC inhibitor (G\u00f6 6983) or a Ca2+ chelating agent did not affect the quercetin-stimulated Cl\u2212 secretion. On the other hand, a PTK inhibitor (AG18) significantly diminished the stimulatory action of quercetin on Cl\u2212 secretion without inhibitory effects on apical Cl\u2212 conductance, suggesting that a PTK-mediated pathway is involved in the stimulatory action of quercetin. The quercetin action on Cl\u2212 secretion was suppressed with brefeldin A (BFA, an inhibitor of vesicular transport from ER to Golgi), and the BFA-sensitive Cl\u2212 secretion was not observed in the presence of an epidermal growth factor receptor (EGFR) kinase inhibitor (AG1478), suggesting that quercetin stimulates Cl\u2212 secretion by causing the EGFR kinase-mediated translocation of NKCC1 or an NKC1-activating factor to the basolateral membrane in human airway epithelial Calu-3 cells. However, the surface density of NKCC1 was not increased by quercetin, but quercetin elevated the activity of NKCC1. These observations indicate that quercetin stimulates Cl\u2212 secretion by activating NKCC1 via translocation of an NKCC1-activating factor through an EGFR kinase-dependent pathway.<\/jats:p>","DOI":"10.1165\/rcmb.2008-0338oc","type":"journal-article","created":{"date-parts":[[2009,2,27]],"date-time":"2009-02-27T21:51:18Z","timestamp":1235771478000},"page":"688-695","source":"Crossref","is-referenced-by-count":23,"title":["Quercetin Stimulates Na+\/K+\/2Cl\u2212 Cotransport via PTK-Dependent Mechanisms in Human Airway Epithelium"],"prefix":"10.1093","volume":"41","author":[{"given":"Junji","family":"Asano","sequence":"first","affiliation":[{"name":"Department of Molecular Cell Physiology"},{"name":"Department of Otolaryngology-Head and Neck Surgery, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Niisato","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell 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