Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 21, Issue 15, Pages 2639-2648Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E09-12-1004
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Funding
- National Institutes of Health [HL73856, DK35124, DK86125, EB00415, EY13574, DK72517]
- Cystic Fibrosis Foundation
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Chloride secretion by airway epithelial cells is defective in cystic fibrosis (CF). The conventional paradigm is that CFTR is activated through cAMP and protein kinase A (PKA), whereas the Ca2+-activated chloride channel (CaCC) is activated by Ca2+ agonists like UTP. We found that most chloride current elicited by Ca2+ agonists in primary cultures of human bronchial epithelial cells is mediated by CFTR by a mechanism involving Ca2+ activation of adenylyl cyclase I (AC1) and cAMP/ PKA signaling. Use of selective inhibitors showed that Ca2+ agonists produced more chloride secretion from CFTR than from CaCC. CFTR-dependent chloride secretion was reduced by PKA inhibition and was absent in CF cell cultures. Ca2+ agonists produced cAMP elevation, which was blocked by adenylyl cyclase inhibition. AC1, a Ca2+/calmodulin-stimulated adenylyl cyclase, colocalized with CFTR in the cell apical membrane. RNAi knockdown of AC1 selectively reduced UTP-induced cAMP elevation and chloride secretion. These results, together with correlations between cAMP and chloride current, suggest that compartmentalized AC1-CFTR association is responsible for Ca2+/cAMP cross-talk. We further conclude that CFTR is the principal chloride secretory pathway in non-CF airways for both cAMP and Ca2+ agonists, providing a novel mechanism to link CFTR dysfunction to CF lung disease.
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