TMEM16A (anoctamin 1, Ano1), a member of a family of 10 homologous proteins, has been shown to form an essential component of Ca2+‐activated CU channels. TMEM16A‐null mice exhibit severe defects in epithelial transport along with tracheomalacia and death within 1 mo after birth. Despite its outstanding physiological significance, the mechanisms for activation of TMEM16A remain obscure. TMEM16A is activated on increase in intracellular Ca2+, but it is unclear whether Ca2+ binds directly to the channel or whether additional components are required. We demonstrate that TMEM16A is strictly membrane localized and requires cytoskeletal interactions to be fully activated. Despite the need for cytosolic ATP for full activation, phosphorylation by protein kinases is not required. In contrast, the Ca2+ binding protein calmodulin appears indispensable and interacts physically with TMEM16A. Openers of small‐ and intermediate‐conductance Ca2+‐activated potassium channels known to interact with calmodulin, such as 1‐EBIO, DCEBIO, or riluzole, also activated TMEM16A. These results reinforce the use of these compounds for activation of electrolyte secretion in diseases such as cystic fibrosis.—Tian, Y., Kongsuphol, P., Hug, M., Ousingsawat, J., Witzgall, R., Schreiber, R., Kunzelmann, K. Calmodulin‐dependent activation of the epithelial calcium‐dependent chloride channel TMEM16A. FASEB J. 25, 1058–1068 (2011). http://www.fasebj.org
