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Model for CaSR-mediated abrogation of secretagogue effects on fluid transport by colonic crypts. cAMP and cGMP are generated by activation of receptors coupled to adenylyl cyclase (AC) and guanylyl cyclase (GC), respectively. Stimulation of either receptor pathway [guanylin or STa toxin for cGMP; cholera toxin or forskolin (FSK) for cAMP] enhances fluid secretion and reduces fluid absorption. Activation of the CaSR by Ca2+ or R-568 stimulates phospholipase C (PLC) activity that generates IP3, resulting in the release of Ca2+ from thapsigargin-sensitive stores. Ca2+-dependent activation of phosphodiesterases (PDE) in crypt cells metabolizes cyclic nucleotides and reverses the effect of secretagogues on fluid transport.