A novel family of putative Ca²⁺ dependent chloride channels, the TMEM16 proteins, has been identified recently. TMEM16A and its closest paralog TMEM16B produce Ca²⁺ activated Cl^- currents when expressed in salamander oocytes and HEK293 cells. These current reflect properties of native CaCCs, such as time and voltage dependence, anion selectivity and pharmacological properties. The family of TMEM16 proteins comprises 10 different proteins which exist as different splice variants. Thus TMEM16 proteins may produce a variety of Ca²⁺ activated Cl^- channels with slightly different biophysical properties in epithelial and non-epithelial cells. In situ hybridization and immunohistochemistry detected TMEM16A in epithelial acinar cells from various glands such as pancreas, salivary glands and mammary gland. Less clear is the expression of TMEM16A in airways and intestine. Results from cultured airway epithelial cells in which expression of endogenous TMEM16A was knocked down by siRNA, suggest a role of TMEM16A calcium-dependent chloride secretion. However as Tmem16a expression in the epithelium of the trachea and lungs changes remarkably during development, the functional role of TMEM16A in the postnatal lung is not clear. As reported recently knockout of TMEM16Aa in mice leads to death within one month of birth, most like due to severe tracheomalacia with gaps in the tracheal cartilage rings along the entire length of the trachea. Thus Tmem16a was identified as a novel regulator of epithelial and smooth muscle cell organization in murine development. Using this model, we examined ion transport in various epithelia tissues such as trachea, colon, pancreatic and submandibular acinar cells. TMEM16A -/- pups typically died within the first 3 to 4 days after birth, which required examination of the tissues at an early postnatal stage. The preliminary results demonstrate impaired Ca²⁺ dependent Cl^- secretion in different epithelial tissues.

Supported by DFG SFB699A6/A7 and DFG KU 756/8-2