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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Regulation of CFTR channels by HCO₃^–-sensitive soluble adenylyl cyclase in human airway epithelial cells

Department of Biology, Hong Kong University of Science and Technology, Kowloon, Hong Kong, People's Republic of China

Submitted 21 December 2004 ; accepted in final form 14 June 2005

CFTR channels conduct HCO₃^– in addition to Cl^– in airway epithelial cells. A defective HCO₃^–-transporting function of CFTR may underlie the pathogenesis of cystic fibrosis. In the present study, we have investigated whether a HCO₃^–-sensitive soluble adenylyl cyclase (sAC) is functionally coupled with CFTR and thus forms an autoregulatory mechanism for HCO₃^– transport in human airway epithelial Calu-3 cells. A reverse transcriptase-polymerase chain reaction showed that transcripts of both full-length and truncated sACs are present in Calu-3 cells. Truncated sAC protein is the predominant, if not the only, isoform expressed in Calu-3 cells. HCO₃^– stimulated a modest increase in cAMP production, and the increase was sensitive to 2-hydroxyestradiol (2-HE), a sAC inhibitor, but not to SQ22,536, a blocker of conventional transmembrane adenylyl cyclases. These results suggest that sAC is functional in Calu-3 cells. Adding 25 mM HCO₃^– to the bath stimulated CFTR-mediated whole cell currents in the absence, but not in the presence, of 2-HE. In cell-attached membrane patches, 25 or 50 mM HCO₃^– in the bath markedly increased the product of channel number and open probability of CFTR, and this activation was attenuated by 2-HE. These findings demonstrate that sAC signaling pathway is involved in the regulation of CFTR function in human airway epithelium and thereby provides a link between the level of intracellular HCO₃^–/CO₂ and the modulation of HCO₃^–-conductive CFTR function by cAMP/PKA.

cystic fibrosis transmembrane conductance regulator; bicarbonate; adenosine 3',5'-cyclic monophosphate; 2-hydroxyestradiol

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