title: The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction.
abstract: Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (neurokinin receptor 1, NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r(-/-) mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial nucleus was inhibited by circulating estradiol but did not colocalize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons.
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension (V.M.N., S.S., R.S.C., U.B.K.), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; Department of Physiology and Pharmacology (M.A.B., O.K.R.), Oregon Health and Science University, Portland, Oregon 97239; Department of Cell Biology, Physiology, and Immunology (S.L., L.P., M.T.-S.), University of Córdoba; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (S.L., L.P., M.T.-S.), Instituto de Salud Carlos III; and Instituto Maimónides de Investigaciones Biomédicas and Hospital Universitario Reina Sofia (S.L., L.P., M.T.-S.), 14004 Córdoba, Spain; Department of Obstetrics and Gynecology (S.S.), Pamukkale University School of Medicine, Denizli, 20020 Turkey; and Massachusetts General Hospital and Harvard Medical School (C.T., S.B.S.), Boston, Massachusetts 02114.
authors.forename: Víctor M
authors.initials: VM
authors.lastname: Navarro
authors.forename: Martha A
authors.initials: MA
authors.lastname: Bosch
authors.forename: Silvia
authors.initials: S
authors.lastname: León
authors.forename: Serap
authors.initials: S
authors.lastname: Simavli
authors.forename: Cadence
authors.initials: C
authors.lastname: True
authors.forename: Leonor
authors.initials: L
authors.lastname: Pinilla
authors.forename: Rona S
authors.initials: RS
authors.lastname: Carroll
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
authors.forename: Oline K
authors.initials: OK
authors.lastname: Rønnekleiv
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
mesh_terms: D000818:Animals; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D059648:Kisspeptins / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015288:Neurokinin A / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D018039:Receptors, Tachykinin / Q000819:agonists; D012098:Reproduction; D013373:Substance P / Q000378:metabolism*
chemical_list: C491407:Kiss1 protein, mouse; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018039:Receptors, Tachykinin; D013373:Substance P; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D015288:Neurokinin A; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone