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Am J Physiol Cell Physiol 284: C1114-C1122, 2003. First published January 8, 2003; doi:10.1152/ajpcell.00400.2002
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Vol. 284, Issue 5, C1114-C1122, May 2003

HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>-dependent soluble adenylyl cyclase activates cystic fibrosis transmembrane conductance regulator in corneal endothelium

Xing Cai Sun1, Chang-Bin Zhai1, Miao Cui1, Yanqiu Chen2, Lonny R. Levin2, Jochen Buck2, and Joseph A. Bonanno1

1 School of Optometry, Indiana University, Bloomington, Indiana 47405; and 2 Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021

cAMP-dependent activation of the cystic fibrosis transmembrane conductance regulator (CFTR) regulates fluid transport in many tissues. Secretion by the corneal endothelium is stimulated by cAMP and dependent on HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>. We asked whether HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> can secondarily increase CFTR permeability in bovine corneal endothelial cells (BCEC) by activating soluble adenylyl cyclase (sAC). Immunofluorescence suggests that sAC is distributed throughout the cytoplasm. HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> (40 mM) increased cAMP concentration 42% in the presence of 50 µM rolipram (a phosphodiesterase 4 inhibitor), and a standard HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> Ringer solution (28.5 mM) increased apical Cl- permeability by 78% relative to HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>-free solution. The HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>-dependent increase in Cl- permeability was reduced 60% by 20 mM NaHSO3 (a weak agonist of sAC). NaHSO3 alone increased apical Cl- permeability by only 13%. The HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>-dependent increase in Cl- permeability was reduced 57% in the presence of 50 µM Rp-adenosine 3',5'-cyclic monophosphorothioate, and 86% by 50 µM 5-nitro-2-(3-phenylpropyl-amino)benzoic acid but unaffected by 200 µM apical H2DIDS. CFTR phosphorylation was increased 23, 150, and 32% by 20 mM HSO<UP><SUB>3</SUB><SUP>−</SUP></UP>, 28.5 mM HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>, and 28.5 mM HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> + 20 mM HSO<UP><SUB>3</SUB><SUP>−</SUP></UP>, respectively. Activation of apical Cl- permeability by 5 µM genistein was increased synergistically by HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> over that due to genistein and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> alone. We conclude that HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>-stimulated sAC is a form of autocrine signaling that contributes to baseline cAMP production, thereby affecting baseline CFTR activity in BCEC. This form of autocrine signaling may be important in tissues that express sAC and exhibit robust HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> influx (e.g., ocular ciliary epithelium, choroid plexus, and airway epithelium).

chloride transport; cAMP; CFTR phosphorylation


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