Serotonin is a neurotransmitter that alters the hypothalamic-pituitary-adrenal axis. To date, however, the molecular mechanisms underlying die role of serotonin in hormone secretion have remained largely unclear. In this study, we report that serotonin activates phospholipase C (PLC) γ1 in an Src-dependent manner in hypothalamic GT1-7 cells, and that pretreatment with either 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazole P, 4-d] pyrimidine, an Src-kinase inhibitor, or U73122, a PLC inhibitor, attenuates the serotonin-induced increase in calcium levels. Also, PLCγ1 binds to c-Src through the Src-homology (SH) 223 domain upon serotonin treatment. Moreover, calcium increase is alleviated in the cells transiently expressing SH223 domain-deleted PLCγ1 or lipase inactive mutant PLC γ1, as compared with cells transfected with wild-type PLC γ1. 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 (GnRI-1). In addition, the results of our small-interfering RNA experiment confirm that endogenous PLC γ1 is a prerequisite for serotonin-mediated signaling pathways. Taken together, our findings demonstrate that serotonin stimulates the release of GnRH through the Src-PLC γ1 pathway, via the modulation of intracellular calcium levels.
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