TMEM16A Ca²⁺-activated Cl^- channel: Functional interactions with cytoskeletal and membrane-associated proteins

The calcium-activated chloride (Cl_Ca) channel TMEM16A (also known as ANO1) is widely expressed in epithelial cells, interstitial cells of Cajal, nociceptive neurons and smooth muscle cells, where it plays essential roles in ion transport, neurotransmission and smooth muscle contraction. Dysfunction of TMEM16A channels contributes to the development and progression of a wide range of diseases. TMEM16A channels embedded in the plasma membrane are continuously exposed to extracellular or intracellular physical stresses, including mechanical stimulation, osmotic pressure, shear stress and changes in cell volume, as well as chemical stresses such as increases in cytosolic Ca²⁺ concentration, pH fluctuations and hypoxia. To maintain appropriate and adaptive responses under these conditions, TMEM16A channels interact with cytoskeletal and membrane-associated proteins that regulate their expression, localisation, stability and function. In particular, cytoskeletal components (the actin cytoskeleton and microtubules), scaffold proteins (the ezrin-radixin-moesin complex), caveolar structures (caveolins and cholesterol), gap junction proteins (connexins) and auxiliary channel subunits have emerged as critical modulators of TMEM16A channel expression and activity, especially in vascular smooth muscle cells. A comprehensive understanding of these functional interactions may provide new insights into the physiological and pathological roles of TMEM16A Cl_Ca channels and may facilitate the development of novel therapeutic strategies for TMEM16A-associated diseases.