Molecular Mechanism of TMEM16A CA2+-Activated Chloride Channel Desensitization

Abstract

TMEM16A forms the long-sought after calcium-activated chloride channel (CaCC) that is highly expressed in various tissues such as dorsal root ganglia (DRGs), epithelial and smooth muscle cells. Extensive studies have demonstrated that the TMEM16A-CaCC plays important roles in mediating nociception, trans-epithelial chloride transport and smooth muscle contraction. Whilst the activation mechanism of the TMEM16A-CaCC has been extensively explored, how the channel activity is regulated in different cell types remains elusive. By studying the molecular mechanism of TMEM16A-CaCC desensitization, a well-documented characteristic of CaCCs, we aim to understand how the TMEM16A-CaCC is regulated at molecular and cellular levels. Our findings will not only illustrate the desensitization mechanism of the TMEM16A-CaCC channel, but add new insights on understanding the channel activation mechanism. As the desensitization severely hampers the biophysical characterization of TMEM16A-CaCC properties, our findings will provide a solution to prevent CaCC desensitization and thus facilitate the structure-function study of the TMEM16 channels.