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Norepinephrine Stimulates Mitogen-Activated Protein Kinase Activity in GT1–1 Gonadotropin-Releasing Hormone Neuronal Cell Lines

Department of Obstetrics and Gynecology, Osaka University Medical School (T.S., M.O., Y.K., A.K., K.M., H.I., A.M., Y.M.), 2–2 Yamadaoka, Suita-shi, Osaka 565; and the Department of Obstetrics and Gynecology, Kanazawa University Medical School (K.K., M.I.), 13–1 Takaramachi Kanazawa-shi, Ishikawa 920, Japan; and the Division of Endocrinology, Children’s Hospital Medical Center, and Perinatal Research Institute, University of Cincinnati College of Medicine (Y.K.), Cincinnati, Ohio 45229

Address all correspondence and requests for reprints to: Dr. Masahide Ohmichi, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565, Japan.

The GT1–1 GnRH neuronal cell lines exhibit highly differentiated properties of GnRH neurons. We have used GT1–1 cells to study the roles of norepinephrine (NE), membrane depolarization, calcium influx, and phorbol esters in the regulation of mitogen-activated protein (MAP) kinase. NE, which is known to stimulate the release of GnRH, induced MAP kinase activity, the tyrosine phosphorylation of MAP kinase, and MAP kinase kinase activity. Forskolin led to activation of MAP kinase comparable with that induced by NE, and a selective inhibitor of cAMP-dependent protein kinase, H8, attenuated the NE-induced activation of MAP kinase. On the other hand, elimination of extracellular calcium by EGTA completely blocked NE-induced tyrosine phosphorylation of MAP kinase, and a selective inhibitor of calcium/calmodulin-dependent protein kinase, KN-62, attenuated the NE-induced activation of MAP kinase. Furthermore, depolarization of GT1–1 cells with 75 mM KCl, 10 µM BayK 8644, or 1 µM calcium ionophore (A23187) induced rapid tyrosine phosphorylation of MAP kinase. The omission of calcium from the extracellular medium completely abolished these effects of tyrosine phosphorylation of MAP kinase. Phorbol 12-myristate 13-acetate (PMA) also induced MAP kinase activity, but pretreatment of the cultured cells with PMA to down-regulate protein kinase C did not abolish the activation of MAP kinase by NE. In addition, although phosphorylation of Raf-1 kinase was stimulated by PMA, this phosphorylation was not induced by either NE or A23187. These results demonstrate that NE activates MAP kinase directly in GT1–1 cells, and that the effect of NE is mediated by increase in the cAMP level and by calcium influx, but not by PMA-sensitive protein kinase C or Raf-1 kinase.

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