title: Neurokinin B causes acute GnRH secretion and repression of GnRH transcription in GT1-7 GnRH neurons.
abstract: Genetic studies in human patients with idiopathic hypogonadotropic hypogonadism (IHH) identified mutations in the genes that encode neurokinin B (NKB) and the neurokinin 3 receptor (NK3R). However, determining the mechanism whereby NKB regulates gonadotropin secretion has been difficult because of conflicting results from in vivo studies investigating the luteinizing hormone (LH) response to senktide, a NK3R agonist. NK3R is expressed in a subset of GnRH neurons and in kisspeptin neurons that are known to regulate GnRH secretion. Thus, one potential source of inconsistency is that NKB could produce opposing direct and indirect effects on GnRH secretion. Here, we employ the GT1-7 cell model to elucidate the direct effects of NKB on GnRH neuron function. We find that GT1-7 cells express NK3R and respond to acute senktide treatment with c-Fos induction and increased GnRH secretion. In contrast, long-term senktide treatment decreased GnRH secretion. Next, we focus on the examination of the mechanism underlying the long-term decrease in secretion and determine that senktide treatment represses transcription of GnRH. We further show that this repression of GnRH transcription may involve enhanced c-Fos protein binding at novel activator protein-1 (AP-1) half-sites identified in enhancer 1 and the promoter, as well as chromatin remodeling at the promoter of the GnRH gene. These data indicate that NKB could directly regulate secretion from NK3R-expressing GnRH neurons. Furthermore, whether the response is inhibitory or stimulatory toward GnRH secretion could depend on the history or length of exposure to NKB because of a repressive effect on GnRH transcription.
authors: Department of Reproductive Medicine and the Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92093-0674, USA.
authors: Christine A
authors: CA
authors: Glidewell-Kenney
authors: Paul P
authors: PP
authors: Shao
authors: Anita K
authors: AK
authors: Iyer
authors: Anna M H
authors: AM
authors: Grove
authors: Jason D
authors: JD
authors: Meadows
authors: Pamela L
authors: PL
authors: Mellon
mesh_terms: D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001665:Binding Sites; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015287:Neurokinin B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D018042:Receptors, Neurokinin-3 / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D018042:Receptors, Neurokinin-3; D018808:Transcription Factor AP-1; C054724:senktide; D013373:Substance P; D007987:Gonadotropin-Releasing Hormone; D015287:Neurokinin B
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