Ca ²⁺ ‐Activated Cl ⁻ Channels

Ca 2+ ‐activated Cl − channels (CaCCs) are plasma membrane proteins involved in various important physiological processes. In epithelial cells, CaCC activity mediates the secretion of Cl − and of other anions, such as bicarbonate and thiocyanate. In smooth muscle and excitable cells of the nervous system, CaCCs have an excitatory role coupling intracellular Ca 2+ elevation to membrane depolarization. Recent studies indicate that TMEM16A (transmembrane protein 16 A or anoctamin 1) and TMEM16B (transmembrane protein 16 B or anoctamin 2) are CaCC‐forming proteins. Induced expression of TMEM16A and B in null cells by transfection causes the appearance of Ca 2+ ‐activated Cl − currents similar to those described in native tissues. Furthermore, silencing of TMEM16A by RNAi causes disappearance of CaCC activity in cells from airway epithelium, biliary ducts, salivary glands, and blood vessel smooth muscle. Mice devoid of TMEM16A expression have impaired Ca 2+ ‐dependent Cl − secretion in the epithelial cells of the airways, intestine, and salivary glands. These animals also show a loss of gastrointestinal motility, a finding consistent with an important function of TMEM16A in the electrical activity of gut pacemaker cells, that is, the interstitial cells of Cajal. Identification of TMEM16 proteins will help to elucidate the molecular basis of Cl − transport.