CaCC

Calcium-activated chloride channels (CaCCs) are a group of chloride channels that open in response to rises in intracellular calcium and conduct Cl- across the cell membrane. They play a central role in controlling cell excitability and transepithelial fluid transport, linking calcium signaling to chloride movement and water flow.

The most studied CaCCs belong to two main families. The TMEM16 (anoctamin) family includes TMEM16A (also known as ANO1), which is widely recognized as a principal CaCC in many tissues, particularly airway and intestinal epithelia. TMEM16A and related family members can form Ca2+-activated chloride currents independently of cAMP, and their activity can be modulated by intracellular Ca2+ concentration, membrane voltage, and cellular context. The TMEM16 family also contains other members such as TMEM16B (ANO2), with specialized roles in sensory systems like olfactory neurons. A second major group comprises the bestrophins (BEST1, BEST2), which function as Ca2+-activated chloride channels in the retinal pigment epithelium and other cell types, with mutations in BEST1 linked to retinal disease.

Mechanistically, CaCCs are activated when intracellular Ca2+ binds to the channel or to associated regulatory proteins, inducing conformational changes that open the pore to Cl-. Permeability is governed by the transmembrane Cl- gradient and the channel’s regulatory state. In epithelial tissues, CaCCs contribute to chloride secretion and, consequently, water movement, influencing mucociliary clearance in airways and fluid balance in the gut. In sensory and neural tissues, CaCCs affect excitability and signal transduction.

Clinical and physiological relevance includes potential targets for treating diseases involving mucus overproduction or impaired secretion, such as cystic fibrosis–related conditions and certain retinal disorders. Research continues to define tissue-specific roles, regulatory mechanisms, and pharmacological modulators of CaCCs.