title: Serotonin stimulates GnRH secretion through the c-Src-PLC gamma1 pathway in GT1-7 hypothalamic cells.
abstract: Serotonin is a neurotransmitter that alters the hypothalamic-pituitary-adrenal axis. To date, however, the molecular mechanisms underlying the role of serotonin in hormone secretion have remained largely unclear. In this study, we report that serotonin activates phospholipase C (PLC) gamma1 in an Src-dependent manner in hypothalamic GT1-7 cells, and that pretreatment with either 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazole [3, 4-d] pyrimidine, an Src-kinase inhibitor, or U73122, a PLC inhibitor, attenuates the serotonin-induced increase in calcium levels. Also, PLC gamma1 binds to c-Src through the Src-homology (SH) 223 domain upon serotonin treatment. Moreover, calcium increase is alleviated in the cells transientlyexpressing SH223 domain-deleted PLC gamma1 or lipase inactive mutant PLC gamma1, as compared with cells transfected with wild-type PLC gamma1. Furthermore, the inhibition of the activities of either PLC or Src results in a significant diminution of the serotonin-induced release of gonadotropin-releasing hormone (GnRH). In addition, the results of our small-interfering RNA experiment confirm that endogenous PLC gamma1 is a prerequisite for serotonin-mediated signaling pathways. Taken together, our findings demonstrate that serotonin stimulates the release of GnRH through the Src-PLC gamma1 pathway, via the modulation of intracellular calcium levels.
authors.affiliation: Division of Molecular and Life Science, Department of Life Science, Pohang University of Science and Technology, San31 Hyoja-Dong Nam-Gu Pohang, Kyungbuk 790-784, South Korea.
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Sanatombi
authors.initials: S
authors.lastname: Yumkham
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Gi Hoon
authors.initials: GH
authors.lastname: Son
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D004963:Estrenes / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D047468:Immunoprecipitation; D008049:Lipase / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection / Q000379:methods; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: C412373:AG 1879; D004963:Estrenes; D011743:Pyrimidines; D011760:Pyrrolidinones; D034741:RNA, Small Interfering; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D012701:Serotonin; D007987:Gonadotropin-Releasing Hormone; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; D008049:Lipase; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium