TMEM16A (also known as anoctamin 1, ANO1) is the molecular basis of the calcium‐activated chloride channels, with ten transmembrane segments. Recently, atomic structures of the transmembrane domains of mouse TMEM16A (mTMEM16A) were determined by single‐particle electron cryomicroscopy. This gives us a solid ground to discuss the electrophysiological properties and functions of TMEM16A. TMEM16A is reported to be dually regulated by Ca2+ and voltage. In addition, the dysfunction of TMEM16A has been found to be involved in many diseases including cystic fibrosis, various cancers, hypertension, and gastrointestinal motility disorders. TMEM16A is overexpressed in many cancers, including gastrointestinal stromal tumors, gastric cancer, head and neck squamous cell carcinoma (HNSCC), colon cancer, pancreatic ductal adenocarcinoma, and esophageal cancer. Furthermore, overexpression of TMEM16A is related to the occurrence, proliferation, and migration of tumor cells. To date, several studies have shown that many natural compounds and synthetic compounds have regulatory effects on TMEM16A. These small molecule compounds might be novel drugs for the treatment of diseases caused by TMEM16A dysfunction in the future. In addition, recent studies have shown that TMEM16A plays different roles in different diseases through different signal transduction pathways. This review discusses the topology, electrophysiological properties, modulators and functions of TMEM16A in mediates nociception, gastrointestinal dysfunction, hypertension, and cancer and focuses on multiple regulatory mechanisms regarding TMEM16A.

The gating of Kir channels depends critically on phosphatidylinositol 4,5-bisphosphate (PIP2), but the detailed mechanism by which PIP2 regulates Kir channels remains obscure. Here, we performed a series of Targeted molecular dynamics simulations on the full-length Kir2.1 channel and, for the first time, were able to achieve the transition from the closed to the open state. Our data show that with the upward motion of the cytoplasmic domain (CTD) the structure of the C-Linker changes from a loop to a helix. The twisting of the C-linker triggers the rotation of the CTD, which induces a small downward movement of the CTD and an upward motion of the slide helix toward the membrane that pulls the inner helix gate open. At the same time, the rotation of the CTD breaks the interaction between the CD- and G-loops thus releasing the G-loop. The G-loop then bounces away from the CD-loop, which leads to the opening of the G-loop gate and the full opening of the pore. We identified a series of interaction networks, between the N-terminus, CD loop, C linker and G loop one by one, which exquisitely regulates the global conformational changes during the opening of Kir channels by PIP2.

Calcium‐activated chloride channels (CaCCs) are ion channels with key roles in physiological processes. They are abnormally expressed in various cancers, including esophageal squamous cell cancer, head and neck squamous cell carcinoma, colorectal cancer, and gastrointestinal stromal tumors. The CaCC component TMEM16A/ANO1 was recently shown to be overexpressed in lung adenocarcinoma cells and may serve as a tumorigenic protein. In this study, we determined that matrine is a potent TMEM16A inhibitor that exerts anti‐lung adenocarcinoma effects. Patch clamp experiments showed that matrine inhibited TMEM16A current in a concentration‐dependent manner with an IC 50 of 27.94 ± 4.78 μM. Molecular simulation and site‐directed mutation experiments demonstrated that the matrine‐sensitive sites of the TMEM16A channel involve the amino acids Y355, F411, and F415. Results of cell viability and wound healing assays showed that matrine significantly inhibited the proliferation and migration of LA795 cells, which exhibit high TMEM16A expression. In contrast, matrine has only weak inhibitory effect on CCD‐19Lu and HeLa cells lacking TMEM16A expression. Matrine‐induced effects on the proliferation and migration of LA795 cells were abrogated upon shRNA‐mediated TMEM16A knockdown in LA795 cells. Finally, in vivo experiments demonstrated that matrine dramatically inhibited the growth of lung adenocarcinoma xenograft tumors in mice but did not affect mouse body weight. Collectively, these data indicate that matrine is an effective and safe TMEM16A inhibitor and that TMEM16A is the target of matrine anti‐lung adenocarcinoma activity. These findings provide new insight for the development of novel treatments for lung adenocarcinoma.