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Stimulation of Luteinizing Hormone-Releasing Hormone (LHRH) Gene Expression in GT_1–7 Cells by Its Metabolite, LHRH-(1–5)

Department of Obstetrics and Gynecology (T.J.W.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814; Fishberg Research Center for Neurobiology (T.J.W., M.J.G., J.L.R.), Mount Sinai School of Medicine, New York, New York 10029; and Department of Molecular and Cellular Biology (S.K.M.), Baylor College of Medicine, Houston, Texas 77005

Address all correspondence and requests for reprints to: T. J. Wu, Department of Obstetrics and Gynecology, Room B2020, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814. E-mail: twu{at}usuhs.mil; or James L. Roberts, Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, MC6205, San Antonio, Texas 78229-3900. E-mail: robertsjl0{at}uthscsa.edu

Given the central role of the decapeptide LHRH in reproduction and reproductive behavior, it is important to focus on delineating the possible effects of this gene and its products in the regulation of hormone-dependent reproductive processes. In the female, ovulation is preceded by a marked increase in LHRH release; the increase in LHRH release culminates in a preovulatory LH surge, which coincides with a period of sexual receptivity. In contrast to the belief that the proteolytic metabolism of LHRH serves only as a degradative process that removes excess LHRH and attenuates signal transduction through the LHRH receptor, we hypothesized that a metabolite of the decapeptide, LHRH-(1–5), can directly regulate LHRH neuronal function. This study demonstrates the ability of LHRH-(1–5) peptide to regulate LHRH gene expression in the LHRH neuronal cell line, the GT_1–7 cell. The results show that LHRH-(1–5) stimulated LHRH gene expression at the posttranscriptional level. In contrast to the LHRH suppression of its own gene expression, the coadministration of LHRH with the metalloendopeptidase, EC 3.4.24.15, an endopeptidase known to cleave LHRH to form LHRH_1–5, shows a reversal of effect, a stimulation of LHRH gene expression. Finally, the effect of LHRH-(1–5) on LHRH gene expression appears to be mediated by the calcium/calmodulin-dependent protein kinase. The present study supports the hypothesis that the physiological metabolite of LHRH, LHRH-(1–5), is functionally capable of regulating the reproductive neuroendocrine system.

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