Properties of Ca²⁺‐activated Cl⁻ channels (CaCCs). The figure shows the characteristic voltage dependence of Ca²⁺‐activated Cl⁻ currents. Each panel reports a series of membrane currents elicited by voltage steps in the −100 to +100 mV range at a given cytosolic Ca²⁺ concentration. At intermediated Ca²⁺ concentrations (100‐500 nM), the currents are activated mainly by positive membrane potentials. When the Ca²⁺ concentration reaches micromolar levels, CaCC‐dependent currents appear also at negative membrane potentials (taken, with permission, from ref. 165).

The Ca²⁺‐activated Cl⁻ channels (CaCC) role in the airway epithelium. Schematic representation of Cl⁻ transport across the airway epithelium. ATP released from the cell binds to apical or basolateral P2Y2 purinergic receptors that trigger a series of events leading to the production of inositol 1,4,5‐triphosphate (IP₃). IP₃ binds to its receptor on the endoplasmic reticulum resulting in Ca²⁺ release. Ca²⁺ may also enter the cell through plasma membrane calcium channels. On the apical membrane Ca²⁺ leads to activation of CaCC, possibly TMEM16A. On the basolateral membrane, Ca²⁺ activates K⁺ channels that confer the driving force for apical Cl⁻ secretion. Cl⁻ enters the cell through NKCC, the Na⁺/K⁺/2Cl⁻ cotransporter. ATP may be metabolized by membrane‐bound nucleotidases with the consequent production of adenosine, which in turn can bind to an adenosine receptor that leads to intracellular cAMP increase. Binding of different hormones to basolaterally located receptors have similar effects. cAMP induces Cl⁻ secretion through cystic fibrosis transmembrane conductance regulator.

Ca²⁺‐activated Cl⁻ channels (CaCCs) in exocrine glands. Representation of a simplified airway submucosal gland as prototypical exocrine glands. Different hormonal stimuli may trigger Cl⁻ secretion either via a Ca²⁺‐dependent pathway, thus involving CaCC in the mucosal surface or throughout cAMP signaling involving cystic fibrosis transmembrane conductance regulator. The membrane protein introducing Cl⁻ on the basolateral membrane is the Na⁺/K⁺/2Cl⁻ cotransporter. The water molecules that follow Cl⁻ secretion hydrate and push the mucin granules and other macromolecules (e.g., lactoferrin, lysozyme, and defensins) toward the gland duct.

Ca²⁺‐activated Cl⁻ channels (CaCCs) function in smooth muscle. Schematic representation of the ion transport systems involved in Cl⁻ secretion in smooth muscle. Binding of hormones to G‐protein‐coupled receptors activates phospholipase C, which in turn releases inositol 1,4,5‐triphosphate (IP₃). IP₃ initiates release of Ca²⁺ from sarcoplasmic reticulum stores that activates CaCCs. The resulting Cl⁻ exit and membrane depolarization amplifies the Ca²⁺ increase by opening voltage‐dependent Ca²⁺ channels. CaCCs may be also activated through Ca²⁺‐induced Ca²⁺ release. Indeed, activation of clusters of ryanodine receptors inducing localized Ca²⁺ release (Ca²⁺ sparks) leads to opening of CaCCs and thus occurrence of spontaneous transient inward current. As in epithelial cells, Cl⁻ is loaded into smooth muscle troughout the activity of Na⁺/K⁺/2Cl⁻ cotransporter.

Ca²⁺‐activated Cl⁻ channels (CaCCs) in photoreceptors. In the dark, the continuous activity of cyclic nucleotide‐gated channels in the outer segment of photoreceptors, and thus of Na⁺ and Ca²⁺ inflow, leads to cell membrane depolarization. This causes activation of voltage‐gated Ca²⁺ channels in the inner segment and probably also in the synaptic terminal. Intracellular Ca²⁺ increase activates CaCCs/TMEM16B in the synaptic terminal, favoring neurotransmitter release toward second‐order neurons.