Structure-Function of TMEM16 Ion Channels and Lipid Scramblases

The TMEM16 protein family comprises two novel classes of structurally conserved but functionally distinct membrane transporters that function as Ca²⁺-dependent Cl^- channels (CaCCs) or dual functional Ca²⁺-dependent ion channels and phospholipid scramblases. Extensive functional and structural studies have advanced our understanding of TMEM16 molecular mechanisms and physiological functions. TMEM16A and TMEM16B CaCCs control transepithelial fluid transport, smooth muscle contraction, and neuronal excitability, whereas TMEM16 phospholipid scramblases mediate the flip-flop of phospholipids across the membrane to allow phosphatidylserine externalization, which is essential in a plethora of important processes such as blood coagulation, bone development, and viral and cell fusion. In this chapter, we summarize the major methods in studying TMEM16 ion channels and scramblases and then focus on the current mechanistic understanding of TMEM16 Ca²⁺- and voltage-dependent channel gating as well as their ion and phospholipid permeation.