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.