Overlapping pharmacology of Ca2+-activated Cl− and K+ channels

Research into Ca2+-activated Cl− channels is hampered by the inability to decipher their molecular identity and the fact that all extant Cl− channel blockers have effects on other ion channels. Most notably, Cl− channel blockers such as the fenamates (e.g. niflumic acid and flufenamic acid) activate Ca2+-dependent K+ channels, although other pharmacological overlaps have been discovered. In this article, we highlight the complex pharmacology of Ca2+-activated Cl− channels and the caveats associated with using these blockers – a necessary requirement because many researchers use Cl− channel blockers as probes for Cl− channel activity. Moreover, we discuss the argument for a common structural motif between Ca2+-activated Cl− channels and Ca2+-dependent K+ channels, which has led to the possibility that the molecular identity of Cl− channels will be revealed by research in this new direction, in addition to the use of existing candidates such as the CLCA, Bestrophin and tweety genes.