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Inactivation of Melatonin Receptors by Protein Kinase C in Human Prostate Epithelial Cells

Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences (E.G., N.Z.), and the Department of Urology (H.M.), Tel Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Address all correspondence and requests for reprints to: Prof. Nava Zisapel, Ph.D. Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: navazis{at}ccsg.tau.ac.il

The pineal hormone melatonin regulates seasonal reproduction and pubertal development in mammals. We recently found melatonin receptors in the human benign prostate tissue, primarily associated with the microsome-enriched fraction of the epithelial cells. In cultured benign prostate epithelial cells, melatonin, at physiological concentrations, suppressed [³H]thymidine incorporation and cGMP levels. The effects of melatonin were transient, suggesting inactivation of the receptors. In the present study, the possibility of inactivation of the prostate melatonin receptors by protein kinase C (PKC) was explored.

Treatment of the microsome-enriched fraction with crude rat brain PKC in the presence of phorbol 12-myristate 13-acetate (TPA) or CaCl₂ abolished the specific [¹²⁵I]melatonin binding. This effect was prevented by the PKC inhibitor bisindolylmaleimide (GF-109203). [¹²⁵I]Melatonin binding could be reinstated by iodoacetamide treatment.

In benign prostate epithelial cells in culture, TPA pretreatment markedly reduced the apparent affinity of [¹²⁵I]melatonin binding. In addition, TPA ablated the cells responses to melatonin, namely the suppression of [³H]thymidine incorporation and cGMP levels. Pretreatment with GF-109203 prevented the TPA effects on [¹²⁵I]melatonin binding and responses. In addition, GF-109203 slowed down the inactivation of the melatonin-mediated inhibition of [³H]thymidine incorporation.

Taken together, these data show that melatonin receptors are desensitized by PKC and imply that the transient response to melatonin may be the outcome of a direct or indirect melatonin-mediated activation of endogenous PKC.

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