Bestrophin and TMEM16—Ca2+ activated Cl− channels with different functions

In the past, a number of candidates have been proposed to form Ca2+ activated Cl− currents, but it is only recently that two families of proteins, the bestrophins and the TMEM16-proteins, recapitulate reliably the properties of Ca2+ activated Cl− currents. Bestrophin 1 is strongly expressed in the retinal pigment epithelium, but also at lower levels in other cell types. Bestrophin 1 may form Ca2+ activated chloride channels and, at the same time, affect intracellular Ca2+ signaling. In epithelial cells, bestrophin 1 probably controls receptor mediated Ca2+ signaling. It may do so by facilitating Ca2+ release from the endoplasmic reticulum, thereby indirectly activating membrane localized Ca2+-dependent Cl− channels. In contrast to bestrophin 1, the Ca2+ activated Cl− channel TMEM16A (anoctamin 1, ANO1) shows most of the biophysical and pharmacological properties that have been attributed to Ca2+-dependent Cl− channels in various tissues. TMEM16A is broadly expressed in both mouse and human tissues and is of particular importance in epithelial cells. Thus exocrine gland secretion as well as electrolyte transport by both respiratory and intestinal epithelia requires TMEM16A. Because of its role for Ca2+-dependent Cl− secretion in human airways, it is likely to become a prime target for the therapy of cystic fibrosis lung disease, caused by defective cAMP-dependent Cl− secretion. It will be very exciting to learn, how TMEM16A and other TMEM16-proteins are activated upon increase in intracellular Ca2+, and whether the other nine members of the TMEM16 family also form Cl− channels with properties similar to TMEM16A.