Transmembrane Protein 16A (TMEM16A) Is a Ca2+-regulated Cl- Secretory Channel in Mouse Airways

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 similar to 50% CFTR activity and similar to 50% non-Tmem16a activity. Interestingly, the tracheas of both the Tmem16a(-/-) and the CFTR-/- mice exhibited similar congenital cartilaginous defects that may reflect acommon 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 mucusaccumulation. Our data suggest that TMEM16A CaCC-mediated Cl- secretion appears to be necessary for normal airway surface liquid homeostasis.