Cetrorelix, a gonadotropin-releasing hormone antagonist, induces the expression of melatonin receptor 1a in the gonadotropin-releasing hormone neuronal cell line GT1-7.
Melatonin has been implicated in the control of the reproductive system, and the modulatory actions of melatonin on gonadotropin-releasing hormone (GnRH) neurons have been assumed to be indirectly mediated through afferent neurons. However, our previous studies demonstrate sexually dimorphic modulation of A-type gamma-aminobutyric acid (GABA) receptor (GABA(A)R) currents by melatonin in adult rat GnRH neurons and a preferential expression of melatonin 1a receptor (MT1) in male GnRH neurons. Using immortalized GnRH neurons (GT1-7 cells), the present study investigated the mechanism by which the expression of melatonin receptors is regulated in GnRH neurons. Like endogenous GnRH neurons, GT1-7 cells express both GnRH and GnRH receptor mRNAs, indicating that the cells have a self-stimulatory system. A 2-iodomelatonin binding assay and RT-PCR analysis demonstrated that the cells expressed neither MT1 nor MT2. However, treatment of GT1-7 cells with the GnRH antagonist cetrorelix significantly increased 2-iodomelatonin binding and induced a time- and concentration-dependent MT1 mRNA expression. The GABA(A)R currents were then measured using a perforated patch-clamp technique to examine whether the treatment with cetrorelix changed the responses to melatonin. Melatonin augmented the GABA(A)R currents in GT1-7 cells treated with 1 muM cetrorelix for 24 h, while melatonin decreased the currents in the cells not treated with cetrorelix, probably via receptor-independent processes. The present results suggest that GnRH downregulates the expression of MT1 via an autocrine-paracrine mechanism in GT1-7 cells, and modifies the melatonin-induced modulation of GABA(A)R currents. These findings may provide one possible mechanism for the sexually dimorphic responses to melatonin in adult rat GnRH neurons.
Ishii
Hirotaka
H
Department of Physiology, Nippon Medical School, Tokyo, Japan. hirotaka@nms.ac.jp
Sato
Shun
S
Yin
Chengzhu
C
Sakuma
Yasuo
Y
Kato
Masakatsu
M
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D008550:Melatonin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D041681:NIH 3T3 Cells; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D011966:Receptors, LHRH / Q000378:metabolism; D013997:Time Factors
D002492:Central Nervous System Depressants; D006727:Hormone Antagonists; D012333:RNA, Messenger; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D011963:Receptors, GABA-A; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; C044556:2-iodomelatonin; D008550:Melatonin; C062876:cetrorelix