Quercetin Stimulates Na+/K+/2Cl− Cotransport via PTK-Dependent Mechanisms in Human Airway Epithelium

We investigated regulatory mechanisms of Cl− secretion playing an essential role in the maintenance of surface fluid in human airway epithelial Calu-3 cells. The present study reports that quercetin (a flavonoid) stimulated bumetanide-sensitive Cl− secretion with reduction of apical Cl− conductance, suggesting that quercetin stimulates Cl− secretion by activating an entry step of Cl− across the basolateral membrane through Na+/K+/2Cl− 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-14–22 amide), a PKC inhibitor (Go 6983) or a Ca2+ chelating agent did not affect the quercetin-stimulated Cl− secretion. On the other hand, a PTK inhibitor (AG18) significantly diminished the stimulatory action of quercetin on Cl− secretion without inhibitory effects on apical Cl− conductance, suggesting that a PTK-mediated pathway is involved in the sti...