{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNPFFR1, also known as GPR147, serves as the primary receptor for RFamide-related peptides such as RFRP‐3 (the mammalian gonadotropin-inhibitory hormone). In the human hypothalamus and pituitary, NPFFR1 is expressed on gonadotropin-releasing hormone (GnRH) neurons and gonadotrope cells. Activation of NPFFR1 by its ligands leads to suppressed gonadotropin synthesis and release, a mechanism that involves modulation of intracellular Ca²⁺ mobilization. In rodent models, the expression of NPFFR1 as well as its ligands is developmentally regulated with estradiol (E2) emerging as a modulator during the prepubertal period."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central actions, NPFFR1 is expressed in ovarian cells including granulosa-lutein cells of preovulatory follicles and the corpus luteum. In these cells, RFRP‐3 binding to NPFFR1 inhibits gonadotropin-stimulated cAMP accumulation and the expression of the steroidogenic acute regulatory protein, thereby reducing progesterone production. This inhibition is mediated via a pertussis toxin-sensitive Gα(i/o) protein pathway, indicating that NPFFR1 activation plays a significant role in fine-tuning ovarian steroidogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructure–activity studies of RFamide peptides underscore the ligand selectivity challenges for receptors; however, NPFFR1 reliably binds its cognate ligands, affirming its specificity in this signaling family. Moreover, investigations into NPFFR1 gene variants have suggested a potential, though secondary, modulatory influence on pubertal timing. While certain polymorphisms in the NPFFR1 gene did not show a strong association with pubertal disorders, they point to a role for NPFFR1 in the complex regulatory network of reproductive axis development that merits further study."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Takayoshi Ubuka, Kevin Morgan, Adam J Pawson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0008400"}], "href": "https://doi.org/10.1371/journal.pone.0008400"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20027225"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20027225"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Takeshi Iwasa, Toshiya Matsuzaki, Masahiro Murakami, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Developmental changes in the mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) and its cognate receptor GPR147 in the rat hypothalamus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Dev Neurosci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ijdevneu.2011.10.003"}], "href": "https://doi.org/10.1016/j.ijdevneu.2011.10.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22064075"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22064075"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Hajime Oishi, Christian Klausen, George E Bentley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human gonadotropin-inhibitory hormone ortholog RFamide-related peptide-3 suppresses gonadotropin-induced progesterone production in human granulosa cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2012-1066"}], "href": "https://doi.org/10.1210/en.2012-1066"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22691551"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22691551"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "C J G Lima, S C Cardoso, E F L Lemos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutational analysis of the genes encoding RFamide-related peptide-3, the human orthologue of gonadotrophin-inhibitory hormone, and its receptor (GPR147) in patients with gonadotrophin-releasing hormone-dependent pubertal disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuroendocrinol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jne.12207"}], "href": "https://doi.org/10.1111/jne.12207"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25180599"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25180599"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Laurent Rouméas, Jean-Paul Humbert, Séverine Schneider, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effects of systematic N-terminus deletions and benzoylations of endogenous RF-amide peptides on NPFF1R, NPFF2R, GPR10, GPR54 and GPR103."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Peptides (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.peptides.2015.07.016"}], "href": "https://doi.org/10.1016/j.peptides.2015.07.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26211894"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26211894"}]}]}]}