TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca2+ and cell volume

For many years Cl− transport by ion channels that are controlled by intracellular Ca2+ or by cell volume remained enigmatic because their molecular identity was unknown. Recent years, however, have shown remarkable progress, and these channels have been identified as TMEM16A (anoctamin 1), LRRC8A (swell 1), and bestrophin 1 (BEST1), and structural information is already available for the Ca2+-activated channels bestrophin and TMEM16. While the structure of bestrophin revealed it is an anion-permeable pore, only indirect evidence exists that TMEM16 and LRRC8 form anion channels. This review summarizes the most recent information on the structure, function, and physiological relevance of these anion channel proteins, and highlights their overlapping functions and physiological roles.