Intracellular Ca²⁺ and Cl^– Channel Activation in Secretory Cells

Molecular and functional evidence indicates that a variety of Ca²⁺dependent chloride (Cl(Ca)) channels are involved in fluid secretion from secretory epithelial cells in different tissues and species. Most Cl(Ca) channels so far characterized have an I⁻ permeability greater than Cl⁻, and most are sensitive to 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS). Whole-cell Cl(Ca) currents show outward rectification. Single-channel current voltage relationships are linear with conductances ranging from 2 to 30 pS. Some Cl(Ca) channels are blocked by Ca²⁺-calmodulin-dependent protein kinase (CAMKII) inhibitors. Others, such as the Cl(Ca) channels of parotid and submandibular acinar cells, appear to be directly regulated by Ca²⁺. In native cells, the Cl(Ca) channels are located on the apical plasma membrane and activated by localized mechanisms of Ca²⁺ release. This positioning allows the Cl(Ca) channel to respond specifically to localized Ca²⁺ signals that do not invade other regions of the cell. The Cl(Ca) follows the rising phase of the Ca²⁺ signal, but in the falling phase hysteresis occurs where the Cl(Ca) current decays more rapidly than the underlying Ca²⁺. The future elucidation of the identity and mechanisms of regulation of Cl(Ca) channels will be critical to our understanding of stimulus-secretion coupling.