CFTR-adenylyl cyclase I association responsible for UTP activation of CFTR in well-differentiated primary human bronchial cell cultures

Wan Namkung, Walter E. Finkbeiner, A. S. Verkman

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

Abstract

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. Ca 2+ 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 Ca 2+/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.

Original languageEnglish
Pages (from-to)2639-2648
Number of pages10
JournalMolecular Biology of the Cell
Volume21
Issue number15
DOIs
Publication statusPublished - 2010 Aug 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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