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 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.
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27708, USA.
Jason R
JR
Rock
Wanda K
WK
O'Neal
Sherif E
SE
Gabriel
Scott H
SH
Randell
Brian D
BD
Harfe
Richard C
RC
Boucher
Barbara R
BR
Grubb
D000818:Animals; D000831:Animals, Newborn; D000075369:Anoctamin-1; D002118:Calcium / Q000378:metabolism*; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004553:Electric Conductivity; D051379:Mice; D009154:Mutation / Q000235:genetics; D014132:Trachea / Q000378:metabolism* / Q000473:pathology
C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002118:Calcium