Cl- regulation of a Ca(2+)-activated nonselective cation channel in beta-agonist-treated fetal distal lung epithelium.
Nonselective cation (NSC) channels have been identified in the apical membrane of fetal distal lung epithelium (FDLE). However, their physiological role in Na+ transport is uncertain. Because terbutaline, a beta 2-agonist, increases Na+ transport by FDLE, we studied its effect and selected signal transduction mechanisms on NSC channel activity. Using patch-clamp and single-cell imaging techniques, we found that terbutaline activated the NSC channel by 1) increasing its sensitivity to cytosolic Ca2+ concentration ([Ca2+]c) by 100- to 1,000-fold, 2) increasing [Ca2+]c from 35 nM to 3.3 microM, 3) producing a dependency of the NSC channel activity on the cytosolic Cl- concentration ([Cl-]c) at a physiological [Ca2+]c, and 4) inducing a reduction in the [Cl-]c from 45 to 25 mM, which directly activates the beta 2-treated NSC channel. These observations indicate that a beta 2-agonist physiologically activates an amiloride-blockable NSC channel in FDLE through an increase in its sensitivity to [Ca2+]c, resulting in the development of a [Cl-]c dependency at a physiological [Ca2+]c associated with both an increase in [Ca2+]c and a reduction in [Cl-]c. A development of the [Cl-]c dependency and a reduction in [Cl-]c act as a second messenger of the beta-agonist signal transduction pathway in this Na(+)-transporting epithelium.
Tohda
H
H
Division of Respiratory Research, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
Foskett
J K
JK
O'Brodovich
H
H
Marunaka
Y
Y
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002412:Cations / Q000378:metabolism*; D002478:Cells, Cultured; D002712:Chlorides / Q000502:physiology*; D004848:Epithelium / Q000196:embryology; D005333:Fetus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000196:embryology*; D051381:Rats; D017208:Rats, Wistar; D013726:Terbutaline / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D002412:Cations; D002712:Chlorides; D007473:Ion Channels; D013726:Terbutaline; D002118:Calcium