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Apical and Basolateral ATP-Induced Anion Secretion in Polarized Human Airway Epithelia

Division of Respiratory Diseases, Department of Internal Medicine, and Department of Cellular Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Address correspondence to: Yasushi Ito, M.D., Division of Respiratory Diseases, Department of Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: itoyasu{at}med.nagoya-u.ac.jp

The present study investigated mechanisms underlying apical and basolateral P2Y₁-mediated Cl^- secretion in human airway epithelial cells. Apical and basolateral ATP induced short-circuit currents (I_sc) with different properties via P2Y₁ receptors. The former comprised an immediate rise followed by a slow attenuation, whereas the latter was a transient rise with a higher peak and shorter duration (< 2 min). The actions of ATP were simulated by those of ADP, ADPßS, and ATPS. Antagonists of phosphatidylinositol-phospholipase C (U73122, ET-18-OCH₃) were without any effect on the bilateral ATP-induced I_sc, which were, in contrast, attenuated by a phosphatidylcholine-phospholipase C inhibitor (D609) and an adenylate cyclase inhibitor (SQ22536). The responses to ATP from either aspect were also sensitive to an intracellular Ca²⁺ chelator, 1,2-bis (o-amino-phenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra-(acetoxymethyl)-ester, or a Ca²⁺-activated K⁺ channel inhibitor, charybdotoxin, although differential Ca²⁺ signals were concomitant with each reaction. Nystatin permeabilization studies revealed a good correlation between the I_sc and the basolateral K⁺ current rather than the apical Cl^- current under ATP-stimulated conditions. In conclusion, apical and basolateral P2Y₁ receptors couple with both phosphatidylcholine-phospholipase C and adenylate cyclase, leading to Cl^- secretion, whose rate is essentially regulated by the Ca²⁺-activated K⁺ channel–mediated K⁺ conductance. This suggests the importance of this channel in airway mucociliary clearance.

Abbreviations: adenylate cyclase, AC • 1,2-bis (o-amino-phenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra-(acetoxymethyl)-ester, BAPTA-AM • intracellular Ca²⁺ concentration, [Ca²⁺]_i • cystic fibrosis transmembrane conductance regulator, CFTR • charybdotoxin, ChTx • diacylglycerols, DAG • human intermediate conductance, inward-rectifying Ca²⁺-activated K⁺ channel, hIK-1 channel • apical Cl^- current, I_Cl • basolateral K⁺ current, I_K • short-circuit current, I_sc • Ca²⁺-activated K⁺ channel, K_Ca channel • 5-nitro-2-(3-phenylpropylamino)-benzoate, NPPB • phosphate-buffered saline, PBS • phosphatidylcholine-phospholipase C, PC-PLC • potential difference, PD • phosphatidylinositol-phospholipase C, PI-PLC • protein kinase C, PKC • physiologic saline solution, PSS • transepithelial resistance, R_t • uridine 5'-triphosphate, UTP