Membrane Transport, Structure, Function, and Biogenesis
Transmembrane Protein 16A (TMEM16A) Is a Ca2+-regulated Cl Secretory Channel in Mouse Airways*

https://doi.org/10.1074/jbc.C109.000869Get rights and content
Under a Creative Commons license
open access

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 ∼50% CFTR activity and ∼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.

Cited by (0)

*

This work was supported, in whole or in part, by National Institutes of Health Grants P30 Dk065988, P01-HL034322, and SCCOR NIH 5 P50 HL084934. This work was also supported by RDP Grant CFF R0 26-CR037 from the Cystic Fibrosis Foundation.