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A Novel Interaction Between Inhibitory Melatonin Receptors and Protein Kinase C-Dependent Signal Transduction in Ovine Pars Tuberalis Cells¹

Molecular Neuroendocrinology Unit, Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen, Scotland, AB21 9SB, United Kingdom

Address all correspondence and requests for reprints to: Peter J. Morgan, Molecular Neuroendocrinology Unit, Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen, Scotland, AB21 9SB, United Kingdom. E-mail: p.morgan{at}rri.sari.ac.uk

This study revealed an important and unexpected finding: namely, that inhibitory melatonin receptors can inhibit a phorbol 12,13 myristate acetate (PMA)-induced, protein kinase C (PKC)-dependent increase in c-fos messenger RNA expression in ovine pars tuberalis (PT) cells. PMA induces dose-dependent stimulation of c-fos expression that is attenuated by melatonin in a dose-dependent and pertussis toxin-sensitive manner. The effect of 100 nM PMA is blocked by Ro31–8220 (1 µM), yet is not mimicked by 4-PMA (100 nM). PMA (100 nM) induces PKC activity in PT cells (P < 0.05) within 5 min, but melatonin has no effect on this response. PMA (100 nM) stimulates both phospholipase D and mitogen-activated protein kinase (MAPK) (p42/44) activities in PT cells, but melatonin has no effect on these responses. The results indicate that neither of these second-messenger activities contribute to the melatonin-sensitive pathway of c-fos activation. The MEK (MAPK kinase) inhibitor, PD98059 (50 µM), does not block the induction of c-fos by PMA, although at the same dose it inhibits PMA-mediated activation of p42/44 MAPK by 50–70%, and activation by forskolin or insulin-like growth factor-I by 100%. These data suggest that p42/44 MAPK may not be the primary mediator of PKC-dependent c-fos induction. In contrast to the effect of melatonin on PMA-mediated c-fos induction in PT cells, in L cells stably transfected with the sheep Mel1aß receptor, melatonin potentiates the c-fos response in a pertussis toxin-sensitive manner. These data indicate the tissue-specific nature of melatonin receptor signaling, and reveal that a pertussis toxin-sensitive pathway can block PKC-mediated c-fos induction in PT cells.

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