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.
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