Calcium Activated Chloride Channels in Human and Animal Disease

Located in the apical membrane of the airway epithelium is a calcium-activated chloride channel system that allows the flow of chloride ions onto the airway surface. This in part creates the osmotic drive to hydrate the airway surface. Unfortunately, an understanding of the molecular components of this system has progressed slowly. Only recently have the very different TMEM16 and Bestrophin gene family members been identified as conducting pore subunits contributing to calcium activated airway epithelium chloride conductance. However, regulation of these subunits remains virtually unknown. In particular, the regulatory mechanism of the calcium-activated chloride channel modulator, designated CLCA (Loewen et al. Physiol. Rev. 85, 1061-92, 2005), in airway epithelium remains enigmatic. Recent studies demonstrated hCLCA1’s ability to change the single channel conductance of endogenous HEK 293 cell calcium activated chloride channels by lowering the energy barriers for ion translocation through the pore (Hanmann, J. Physiol. 587, 2255-2274, 2009).

Our investigations in this area will give insight into a system which is essential to proper airway hydration in mammalian species for proper airway defense. Finally, a deeper understanding of this basic physiological process will add to a knowledge base to help combat genetic airway diseases such as Cystic Fibrosis and infectious diseases causing pneumonia.