ABSTRACT

The Ca²⁺-signaling pathway plays a crucial role in the regulation of intestinal electrolyte transport; its stimulation leads to the inhibition of Na⁺ and Cl^- absorption and induces a massive secretion of anions, especially of Cl^-. The steps involved in this cascade include the receptor- and G-protein-mediated stimulation of phospholipase C, leading to the generation of inositol-l,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). DAG activates protein kinase C (PKC), which is translocated to the membrane. An alternative pathway involved in PKC stimulation is phospholipase D. IP₃ in turn stimulates the release of intracellularly stored Ca²⁺ followed by an influx of extracellular Ca²⁺ ions via store-operated, non-selective cation channels. In parallel, the Na⁺-Ca²⁺-exchanger is turned off to prevent an extrusion of Ca²⁺. The main action site of Ca²⁺ responsible for the induction of Cl^- secretion are Ca²⁺-dependent K⁺ channels in the basolateral membrane, which upon opening cause a membrane hyperpolarization  enhancing the driving force for Cl^- exit across Cl^- channels in the apical membrane.