Transmembrane Protein 16A (TMEM16A) Is a Ca 2+ -regulated Cl – Secretory Channel in Mouse Airways

Scott H. Randell, Brian D. Harfe, Richard C. Boucher, Jason R. Rock, Sherif E. Gabriel, Wanda K. O'Neal, Barbara R. Grubb
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.
more » ... hen 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.
doi:10.17615/3s0t-9h68 fatcat:tj77sojqffddjcf4drubqzmhyu