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Role of the Second-Messenger Cyclic-Adenosine 5'-Diphosphate-Ribose on Adrenocorticotropin Secretion from Pituitary Cells

Departments of Anesthesiology and Physiology and Biophysics, Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Eduardo Nunes Chini, Signal Transduction Laboratory, Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905. E-mail: chini.eduardo{at}mayo.edu.

We examined the role of the second-messenger cyclic-ADP-ribose (cADPR) on the regulation of ACTH secretion using AtT20 corticotroph tumor cell line. We found that the cADPR antagonist, 8-Br-cADPR, substantially diminished the secretion of ACTH induced by CRH and potassium in these cells, whereas xestospongin C, an inositol 1,4,5-triphosphate receptor antagonist, had no effect. In addition, the cADPR agonist, 3-deaza-cADPR, augmented ACTH secretion. The presence of the components of the cADPR system, namely ryanodine receptor, CD38, and cADPR itself, was determined in AtT20 cells. Furthermore, we observed that antagonists of the ryanodine channel and cADPR system can decrease the potassium-induced Ca²⁺ transients in these cells. These results suggest that cADPR is a second messenger in pituitary cells and regulates ACTH secretion by a mechanism dependent on activation of the ryanodine channel by extracellular Ca²⁺.