TMEM16 Proteins (Anoctamins) in Epithelia

The members of Transmembrane 16 (TMEM16) family, also known as anoctamins, are membrane proteins regulated by cytosolic Ca2+. TMEM16A (ANO1) and TMEM16B (ANO2) are Ca2+-activated Cl− channels, whereas other anoctamins, such as TMEM16F (ANO6), are associated with Ca2+-activated scrambling of membrane glycerophospholipids and sphingolipids. TMEM16F also shows ion channel activity although at very high Ca2+ concentrations. In airway, salivary, biliary, pancreatic, and intestinal epithelial cells, TMEM16A is involved in Cl− and bicarbonate secretion across the apical membrane. This function is directly mediated by TMEM16A as an apical channel. However, TMEM16A may also have an active role in the organization and regulation of compartments involved in Ca2+ signaling. In airway epithelial cells, TMEM16A expression is strongly stimulated by Th2 cytokines, IL-4 and IL-13. This upregulation occurs in mucus-producing goblet cells thus indicating a particular role of TMEM16A in mucus release and expansion.