Calcium-activated chloride channels(CaCCs) were first described in 1980s in Xenopus oocytes, in which they were activated by increasing Ca2+ concentration upon fertilization to prevent polyspermy.Now, it has been found that CaCCs play several important roles in many cells from various types of neurons to epithelium, cardiac muscles and smooth muscles.They participate in many vital biological processes, including cell volume regulation,neuronal and cardiac excitability, smooth muscle contraction and transendothelial ions/fluid transport.Gating mechanisms and permeability are basic issues in ion channel study.We focused on the gating mechanism of calcium-activated chloride channels (CaCCs)/TMEM16A.Some valuable results were obtained by the above work.Whole-cell and excised patch clamp experiments were performed and the results were compared in their activation and rectification modes.Based on the above results, it was proposed that there are two types of activation modes (direct activation and indirect activation) in CaCCs gating mechanism.In excised patch, only direct activation was involved, and just required Ca2+,dwelling in partial activation state and exhibiting outward rectification, wherein maximum activation was achieved only at depolarized voltages.While in whole-cell, both direct and indirect activation were involved, and the latter required multiple signal-transduction reactions.In this mode, the CaCCs could reach full activation state and exhibiting linear rectification character, in which maximum activation currents were produced at both depolarized and hyperpolarized voltages.It will provide some useful clues for the current activation character for the diversity of various channel sources and could be foundation of further pathological and pharmacological research in related diseases.