Typically, ion-channel biophysicists and developmental and cancer biologists rarely attend the same journal clubs. But two studies might change this, one by Caputo et al. on page 590 in this issue (1) and the other by Yang et al.(2). Both studies show that a transmembrane protein, TMEM16A [also called anoctamin-1 (ANO1)], whose expression increases in many tumors, is a calcium (Ca2+)-activated, chloride (Cl−) channel. The Ca2+-activated Cl− channels were first described in the 1980s as mediating the fast block to polyspermy in amphibian oocytes (3). These channels, activated by increases in the concentration of intracellular Ca2+ ions that occur upon fertilization, conduct Cl− ions across the plasma membrane, causing the cell to depolarize and prevent additional sperm entry. Similar channels in many cell types, including mammalian, play roles as diverse as epithelial fluid secretion, amplification of the olfactory receptor potential, and regulation of vascular tone (3). Yet, Ca2+-activated Cl− channels have been “a function in search of a molecule” for more than a decade. Previous claims that other molecules (CLCAs, ClC-3, and tweety) function as Ca2+-activated Cl− channels have been contentious because the ionic currents (electric currents carried by ions) conducted by these proteins do not exhibit the appropriate pharmacology, kinetics, voltage dependence, or Ca2+ sensitivity (3). Bestrophins, which can function as Cl–channels and as regulators of voltage-gated Ca2+ channels, fit the bill more closely, but not exactly (4).

Why has the Ca2+-activated Cl− channel been so hard to find? One reason is that every cell expresses Cl− channels, and the pharmacological tools needed to identify Cl− channels are not very selective. Furthermore, because overexpressing some membrane proteins paradoxically increases the expression of endogenous Cl− channels, heterologous expression of putative Cl− channels can produce false-positives. These obstacles have made it hard to identify candidate Ca2+-activated Cl− channels.