Calcium-activated chloride channel (TMEM16A, Anoctamin-1) (CaCC (for the channel family); TMEM16A or ANO1 (for the principal human gene product))

Calcium-activated chloride channels (CaCCs) are membrane ion channels that open in response to increases in intracellular Ca^2+, allowing chloride ions (Cl^−) to flow across the plasma membrane. The principal molecular entity of CaCCs in mammals is TMEM16A (also known as Anoctamin-1, ANO1, or DOG1), which is widely expressed in epithelial cells, smooth muscle, and sensory tissues. Activation of TMEM16A/CaCCs is crucial for processes such as epithelial fluid secretion, control of smooth muscle excitability and contraction, and sensory signal transduction. TMEM16A has emerged as a promising therapeutic target for diseases such as cystic fibrosis (by compensating for defective CFTR-mediated Cl^− transport), hypertension, stroke, and disorders of gastrointestinal motility. Drugs targeting TMEM16A act by direct pore block, allosteric modulation, or indirect activation via increases in intracellular calcium. Dysregulation of CaCC function is implicated in various diseases, and TMEM16A/DOG1 is used as a biomarker for certain cancers, notably gastrointestinal stromal tumors. While TMEM16A-targeted therapy promises benefit in multiple disease settings, safety risks include disturbances in fluid/electrolyte balance and unintended smooth muscle or epithelial effects due to its broad physiological roles. Caveats: "Calcium-activated chloride channel" refers to a family of channels, but TMEM16A/Anoctamin-1 is the most recognized molecular entity underlying this function in humans, and thus is the canonical form for therapeutic targeting. Some historical gene products (e.g., CLCA, bestrophin) once proposed as CaCCs do not match the functional or molecular properties of native CaCCs or are now classified differently.

Other names

CaCCTMEM16AAnoctamin-1 (ANO1)DOG1 (Discovered on gastrointestinal stromal tumors 1)Calcium-activated chloride channel protein 1

Pore blockade (direct binding in the ion permeation pathway); Allosteric modulation (nonpore binding that alters gating or ion conduction); Indirect activation via increased intracellular Ca^2+; Potentiation or inhibition of channel gating