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J Biol Chem. 2009 May 29;284(22):14875-80. doi: 10.1074/jbc.C109.000869. Epub 2009 Apr 10.

Transmembrane protein 16A (TMEM16A) is a Ca2+-regulated Cl- secretory channel in mouse airways.

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  • 1Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27708, USA.

Abstract

For almost two decades, it has been postulated that calcium-activated Cl(-) channels (CaCCs) play a role in airway epithelial Cl(-) secretion, but until recently, the molecular identity of the airway CaCC(s) was unknown. Recent studies have unequivocally identified TMEM16A as a glandular epithelial CaCC. We have studied the airway bioelectrics of neonatal mice homozygous for a null allele of Tmem16a (Tmem16a(-/-)) to investigate the role of this channel in Cl(-) secretion in airway surface epithelium. When compared with wild-type tracheas, the Tmem16a(-/-) tracheas exhibited a >60% reduction in purinoceptor (UTP)-regulated CaCC activity. Other members of the Tmem16 gene family, including Tmem16f and Tmem16k, were also detected by reverse transcription-PCR in neonatal tracheal epithelium, suggesting that other family members could be considered as contributing to the small residual UTP response. TMEM16A, however, appeared to contribute little to unstimulated Cl(-) secretion, whereas studies with cystic fibrosis transmembrane conductance regulator (CFTR)-deficient mice and wild-type littermates revealed that unstimulated Cl(-) secretion reflected approximately 50% CFTR activity and approximately 50% non-Tmem16a activity. Interestingly, the tracheas of both the Tmem16a(-/-) and the CFTR(-/-) mice exhibited similar congenital cartilaginous defects that may reflect a common Cl(-) secretory defect mediated by the molecularly distinct Cl(-) channels. Importantly, the residual CaCC activity in Tmem16a(-/-) mice appeared inadequate for normal airway hydration because Tmem16a(-/-) tracheas exhibited significant, neonatal, lumenal mucus accumulation. Our data suggest that TMEM16A CaCC-mediated Cl(-) secretion appears to be necessary for normal airway surface liquid homeostasis.

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