Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB077

Poster Communications

Role of TMEM16A in mucus secretion in airways inflammatory diseases

R. Benedetto1, I. Cabrita1, R. Schreiber1, K. Kunzelmann1

1. Physiology, University of Regensburg, Regensburg, Germany.

Cystic Fibrosis (CF) is an inherited disease affecting mucin-producing organs. In fact in CF mucus is particularly viscous and adhesive due to a compromised ions secretion caused by defective channels called CFTRs (cystic fibrosis transmembrane conductance regulators). Mucus hyperproduction causes airway obstruction, reduced mucociliary clearance and chronic inflammation. CFTR is not the only channel responsible for electrolytic balance in secretory epithelia: TMEM16A is a Ca2+activated chloride channel strongly up regulated in CF and asthma, which parallels goblet cell metaplasia. We report that airway epithelial knockout of TMEM16A leads to accumulation of mucus in secretory (Clara) cells and we demonstrate that this channel is indispensable for their basal and ATP-driven mucus release. While acute ATP-induced mucus secretion by airway club cells is strongly compromised in the absence of TMEM16A, the cholinergic mucus secretion due to compound exocytosis is independent of TMEM16A. The present data demonstrate for the first time that the calcium-activated chloride ion channel TMEM16A controlsconstitutiveexocytosis in a ATP-dependent manner. The results provide the basis for an alternative therapeutical target for Cystic Fibrosis, as well as for other inflammatory lung diseases such as asthma and COPD.

Where applicable, experiments conform with Society ethical requirements