Recent advances in TMEM16A: Structure, function, and disease

Abstract

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.

Specific PIP2Binding Promotes Calcium Activation of TMEM16A Chloride Channels

“…One of the most intriguing features of the TMEM16 family proteins is that it's members can transport ions and/or phospholipid, two seemingly distinct classes of substrates, despite highly conserved structures. 3,7 Our previous study of TMEM16F lipid scramblase has suggested a conserved "clam-shell" model of activation for the TMEM16 family proteins. 17 Whether a TMEM16 protein has channel and/or scramblase activities is likely determined by how wide the same pore may be dilated (e.g., see Fig.…”

“…Ca 2+ -activated Clchannels (CaCCs) direct the flow of information from calcium signaling to Cl − current and are involved in numerous physiological functions including neuronal excitation, smooth muscle contraction and airway fluid secretion. 1,2,3 After two decades of searching, the molecular identity of CaCC was finally determined as TMEM16A. 2,4,5,6 TMEM16A, also known as anoctamin-1 (ANO1), belongs to the TMEM16 family of multi-functional proteins that include both CaCC and Ca 2+ -activated lipid scramblase.…”

“…9 TMEM16A has also been also found to be overexpressed in many cancers and is considered a promising anti-cancer drug target. 3 Despite these important roles, the molecular mechanisms of TMEM16A CaCC activation and regulation is only starting to be understood. 3,12 Functional TMEM16A channels are double-barreled homodimers with each monomer harboring a conduction pore that can be activated independently.…”

“…3 Despite these important roles, the molecular mechanisms of TMEM16A CaCC activation and regulation is only starting to be understood. 3,12 Functional TMEM16A channels are double-barreled homodimers with each monomer harboring a conduction pore that can be activated independently. 13 High-resolution structures of TMEM16A have been determined in both the Ca 2+ bound and free states using cryo-EM.…”

Biochemical Inhibition of DOG1/TMEM16A Achieves Antitumoral Effects in Human Gastrointestinal Stromal Tumor Cells In Vitro

“…In a study using several epithelial tumor cell lines, it was discovered that DOG1 degradation was crucial for its antitumoral effects (29). Since then, advancements have been made in the knowledge of CaCC inhibitors possessing not only inhibitory activities but also DOG1 protein degradation properties, reviewed in detail elsewhere (30). Therefore, we sought to evaluate if enhanced DOG1 inhibition would lead to functional antitumoral effects in well-established GIST tumor cell lines.…”