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Role of ATP-purinergic receptor signaling in regulation of ovulation in mammals

Research Project

Project/Area Number 19H03103
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 42010:Animal production science-related
Research InstitutionNagoya University

Principal Investigator

Inoue Naoko  名古屋大学, 生命農学研究科, 准教授 (90377789)

Co-Investigator(Kenkyū-buntansha) 平林 真澄  生理学研究所, 行動・代謝分子解析センター, 准教授 (20353435)
松山 秀一  名古屋大学, 生命農学研究科, 准教授 (50455317)
上野山 賀久  名古屋大学, 生命農学研究科, 准教授 (70324382)
中村 翔  岡山理科大学, 獣医学部, 講師 (50829223)
Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2022: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2021: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2019: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
Keywordsキスペプチン / 排卵 / プリン作動性ニューロン / ATP / プリン受容体 / 性腺刺激ホルモン放出ホルモン(GnRH) / 黄体形成ホルモン(LH) / エストロゲン / 黄体形成ホルモン / GnRH / キスペプチンニューロン / LH / P2X2受容体 / プリン作動性神経
Outline of Research at the Start

本研究の目的は、ほ乳類の雌の排卵を制御する視床下部視索前野/前腹側室周囲核キスペプチンニューロンに発現するプリン受容体に着目し、ATP-プリン受容体シグナリングが排卵中枢であるキスペプチンニューロンを活性化し排卵に至る神経メカニズムを明らかにすることである。一般的に細胞内のエネルギー通貨として知られるATPは、脳内でプリン作動性神経リガンドとして作用するが生殖機能における役割は不明であった。本研究では、ATP-プリン受容体による排卵中枢キスペプチンニューロンの活性化メカニズムを明らかにするとともに、得られた知見の家畜への応用を検証する。

Outline of Final Research Achievements

Kisspeptin neurons in the anterior hypothalamus are responsible for generating a gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) surge and consequent ovulation in mammals. The present study showed that preovulatory levels of estrogen stimulate the activity of purinergic neurons in the hindbrain of female rats. We also found that ATP, which is released as a neurotransmitter from the hindbrain purinergic neurons, acts on kisspeptin neurons in the anterior hypothalamus, causing activation of the kisspeptin neurons and subsequent GnRH/LH surge, and hence ovulation in female rats. These results suggest that hindbrain ATP-purinergic signaling triggers ovulation via the activation of kisspeptin neurons in the anterior hypothalamus in mammals.

Academic Significance and Societal Importance of the Research Achievements

哺乳類において、視床下部前方に存在するキスペプチンニューロンは、種を越えて性腺刺激ホルモン放出ホルモン(GnRH)分泌を促進し排卵を制御する排卵中枢として機能することが知られる。本研究では、ラットにおいてATP-プリン受容体シグナリングが、排卵中枢キスペプチンニューロンの活性化を介して、排卵を誘起することを明らかにした。本研究による知見は、哺乳類における排卵制御メカニズムの一端を明らかにした点で、社会的・学術的に大きな意義がある。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (37 results)

All 2023 2022 2021 2020 2019 Other

All Journal Article (25 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 25 results,  Open Access: 19 results) Presentation (11 results) (of which Invited: 1 results) Remarks (1 results)

  • [Journal Article] Hindbrain adenosine 5-triphosphate (ATP)-purinergic signaling triggers LH surge and ovulation via activation of AVPV kisspeptin neurons in rats2023

    • Author(s)
      Inoue Naoko、Hazim Safiullah、Tsuchida Hitomi、Dohi Yuri、Ishigaki Ren、Takahashi Ai、Otsuka Yuki、Yamada Koki、Uenoyama Yoshihisa、Tsukamura Hiroko
    • Journal Title

      The Journal of Neuroscience

      Volume: 43 Issue: 12 Pages: 2140-2152

    • DOI

      10.1523/jneurosci.1496-22.2023

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Enkephalin-δ opioid receptor signaling mediates glucoprivic suppression of LH pulse and gluconeogenesis in female rats2023

    • Author(s)
      Tsuchida Hitomi、Nonogaki Miku、Takizawa Marina、Inoue Naoko、Uenoyama Yoshihisa、Tsukamura Hiroko
    • Journal Title

      Endocrinology

      Volume: 164 Issue: 3

    • DOI

      10.1210/endocr/bqac216

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dynorphin-κ-opioid receptor signaling, but not μ-opioid receptor signaling, partly mediates the suppression of luteinizing hormone release during late lactation in rats2022

    • Author(s)
      Tsuchida Hitomi、Nonogaki Miku、Inoue Naoko、Uenoyama Yoshihisa、Tsukamura Hiroko
    • Journal Title

      Neuroscience Letters

      Volume: 791 Pages: 136920-136920

    • DOI

      10.1016/j.neulet.2022.136920

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Opioidergic pathways and kisspeptin in the regulation of female reproduction in mammals2022

    • Author(s)
      Uenoyama Yoshihisa、Tsuchida Hitomi、Nagae Mayuko、Inoue Naoko、Tsukamura Hiroko
    • Journal Title

      Frontiers in Neuroscience2022

      Volume: 16

    • DOI

      10.3389/fnins.2022.958377

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of embryo transfer in the musk shrew (<i>Suncus murinus</i>)2022

    • Author(s)
      INOUE Naoko、HOTTA Akinori、GOTO Teppei、HIRABAYASHI Masumi、UENOYAMA Yoshihisa、TSUKAMURA Hiroko
    • Journal Title

      Journal of Reproduction and Development

      Volume: 68 Issue: 5 Pages: 340-344

    • DOI

      10.1262/jrd.2022-003

    • ISSN
      0916-8818, 1348-4400
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cellular and molecular mechanisms regulating the KNDy neuronal activities to generate and modulate GnRH pulse in mammals2022

    • Author(s)
      Ikegami Kana、Watanabe Youki、Nakamura Sho、Goto Teppei、Inoue Naoko、Uenoyama Yoshihisa、Tsukamura Hiroko
    • Journal Title

      Frontiers in Neuroendocrinology

      Volume: 64 Pages: 100968-100968

    • DOI

      10.1016/j.yfrne.2021.100968

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Kisspeptin neurons as a key player bridging the endocrine system and sexual behavior in mammals2022

    • Author(s)
      Nakamura Sho、Watanabe Youki、Goto Teppei、Ikegami Kana、Inoue Naoko、Uenoyama Yoshihisa、Tsukamura Hiroko
    • Journal Title

      Frontiers in Neuroendocrinology

      Volume: 64 Pages: 100952-100952

    • DOI

      10.1016/j.yfrne.2021.100952

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Central μ-Opioid Receptor Antagonism Blocks Glucoprivic LH Pulse Suppression and Gluconeogenesis/Feeding in Female Rats2021

    • Author(s)
      Tsuchida Hitomi、Kawai Narumi、Yamada Koki、Takizawa Marina、Inoue Naoko、Uenoyama Yoshihisa、Tsukamura Hiroko
    • Journal Title

      Endocrinology

      Volume: 162 Issue: 10 Pages: 1-12

    • DOI

      10.1210/endocr/bqab140

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Kisspeptin Neurons and Estrogen?Estrogen Receptor α Signaling: Unraveling the Mystery of Steroid Feedback System Regulating Mammalian Reproduction2021

    • Author(s)
      Uenoyama Yoshihisa、Inoue Naoko、Nakamura Sho、Tsukamura Hiroko
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 17 Pages: 9229-9229

    • DOI

      10.3390/ijms22179229

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Morphological Analysis of the Hindbrain Glucose Sensor-Hypothalamic Neural Pathway Activated by Hindbrain Glucoprivation2021

    • Author(s)
      Sato Marimo、Minabe Shiori、Sakono Takahiro、Magata Fumie、Nakamura Sho、Watanabe Youki、Inoue Naoko、Uenoyama Yoshihisa、Tsukamura Hiroko、Matsuda Fuko
    • Journal Title

      Endocrinology

      Volume: 162 Issue: 9 Pages: 1-18

    • DOI

      10.1210/endocr/bqab125

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator2021

    • Author(s)
      Nagae Mayuko、Uenoyama Yoshihisa、Okamoto Saki、Tsuchida Hitomi、Ikegami Kana、Goto Teppei、Majarune Sutisa、Nakamura Sho、Sanbo Makoto、Hirabayashi Masumi、Kobayashi Kenta、Inoue Naoko、Tsukamura Hiroko
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 5

    • DOI

      10.1073/pnas.2009156118

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mating-induced increase in <i>Kiss1</i> mRNA expression in the anteroventral periventricular nucleus prior to an increase in LH and testosterone release in male rats2020

    • Author(s)
      Watanabe Y., Ikegami K., Nakamura Sho., Uenoyama Y., Ozawa H., Maeda K., Tsukamura H., Inoue N.
    • Journal Title

      Journal of Reproduction and Development

      Volume: 66 Issue: 6 Pages: 579-586

    • DOI

      10.1262/jrd.2020-067

    • NAID

      130007958759

    • ISSN
      0916-8818, 1348-4400
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Seasonal changes in the reproductive performance in local cows receiving artificial insemination in the Pursat province of Cambodia2020

    • Author(s)
      Tep, B., Morita, Y., Matsuyama, S., Ohkura, S., Inoue, N., Tsukamura, H., Uenoyama, Y. and Pheng, V.
    • Journal Title

      Asian-Australasian Journal of Animal Sciences

      Volume: 33 Issue: 12 Pages: 1922-1929

    • DOI

      10.5713/ajas.19.0893

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Paraventricular dynorphin A neurons mediate LH pulse suppression induced by hindbrain glucoprivation in female rats.2020

    • Author(s)
      Hitomi Tsuchida, Parvin Mostari, Koki Yamada, Sae Miyazaki, Yuki Enomoto, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura.
    • Journal Title

      Endocrinology

      Volume: 161(11) Issue: 11 Pages: 1-18

    • DOI

      10.1210/endocr/bqaa161

    • NAID

      120007192020

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Facilitatory and inhibitory role of central amylin administration in the regulation of the gonadotropin-releasing hormone pulse generator activity in goats2020

    • Author(s)
      Kitagawa, Y., Sasaki, T., Suzumura, R., Morishima, A., Tatebayashi, R., Assadullah, Ieda, N., Morita, Y., Matsuyama, S., Inoue, N., Uenoyama, Y. Tsukamura, H. and Ohkura. S.
    • Journal Title

      Neuroscience Letters

      Volume: 736 Pages: 135276-135276

    • DOI

      10.1016/j.neulet.2020.135276

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Testosterone supplementation rescues spermatogenesis and in vitro fertilizing ability of sperm in Kiss1 knockout mice.2020

    • Author(s)
      T. Goto, M. Hirabayashi, Y. Watanabe, M. Sanbo, K. Tomita, N. Inoue, H. Tsukamura, Y. Uenoyama.
    • Journal Title

      Endocrinology

      Volume: - Issue: 9 Pages: 1-11

    • DOI

      10.1210/endocr/bqaa092

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Conditional Kisspeptin Neuron-Specific Kiss1 Knockout With Newly Generated Kiss1-floxed and Kiss1-Cre Mice Replicates a Hypogonadal Phenotype of Global Kiss1 Knockout Mice2020

    • Author(s)
      Kana Ikegami, Teppei Goto, Sho Nakamura, Youki Watanabe, Arisa Sugimoto, Sutisa Majarune, Kei Horihata, Mayuko Nagae, Junko Tomikawa, Takuya Imamura, Makoto Sanbo, Masumi Hirabayashi, Naoko Inoue, Kei-Ichiro Maeda, Hiroko Tsukamura, Yoshihisa Uenoyama
    • Journal Title

      J Reprod Dev.

      Volume: in press Issue: 4 Pages: 359-367

    • DOI

      10.1262/jrd.2020-026

    • NAID

      130007888736

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inducible Kiss1 knockdown in the hypothalamic arcuate nucleus suppressed pulsatile secretion of luteinizing hormone in male mice2020

    • Author(s)
      Shiori Minabe, Sho Nakamura, Eri Fukushima, Marimo Sato, Kana Ikegami, Teppei Goto, Makoto Sanbo, Masumi Hirabayashi, Junko Tomikawa, Takuya Imamura, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei-Ichiro Maeda, Fuko Matsuda
    • Journal Title

      Journal of Reproduction and Development

      Volume: Epub Issue: 4 Pages: 369-375

    • DOI

      10.1262/jrd.2019-164

    • NAID

      130007888724

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of immortalised cell lines derived from female Shiba goat KNDy and GnRH neurones.2020

    • Author(s)
      Suetomi Y, Tatebayashi R, Sonoda S, Munetomo A, Matsuyama S, Inoue N, Uenoyama Y, Takeuchi Y,Tsukamura H, Ohkura S, Matsuda F.
    • Journal Title

      Neuroendocrinology

      Volume: 32(6) Issue: 6 Pages: 12857-12857

    • DOI

      10.1111/jne.12857

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Peripheral administration of SB223412, a selective neurokinin-3 receptor antagonist, suppresses pulsatile luteinizing hormone secretion by acting on the gonadotropin-releasing hormone pulse generator in estrogen-treated ovariectomized female goats.2020

    • Author(s)
      Sasaki T, Sonoda T, Tatebayashi R, Kitagawa Y, Oishi S, Yamamoto K, Fujii N, Inoue N, Uenoyama Y, Tsukamura H, Maeda KI, Matsuda F, Morita Y, Matsuyama S, Ohkura S.
    • Journal Title

      J Reprod Dev

      Volume: - Issue: 4 Pages: 351-357

    • DOI

      10.1262/jrd.2019-145

    • NAID

      130007888728

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Morphological analysis for neuronal pathway from the hindbrain ependymocytes to the hypothalamic kisspeptin neurons2019

    • Author(s)
      Deura C, Minabe S, Ikegami K, Inoue N, Uenoyama Y, Maeda KI, Tsukamura H.
    • Journal Title

      Journal of Reproduction and Development

      Volume: 65 Issue: 2 Pages: 129-137

    • DOI

      10.1262/jrd.2018-122

    • NAID

      130007630928

    • ISSN
      0916-8818, 1348-4400
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ad libitum feeding triggers puberty onset associated with increases in arcuate Kiss1 and Pdyn expression in growth-retarded rats.2019

    • Author(s)
      Majarune S, Pelden Nima, Sugimoto A, Nagae M, Inoue N, Tsukamura H, Uenoyama Y.
    • Journal Title

      J Reprod Dev

      Volume: 65(5) Issue: 5 Pages: 397-406

    • DOI

      10.1262/jrd.2019-048

    • NAID

      130007732090

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Role of kisspeptin neurons as a GnRH surge generator: Comparative aspects in rodents and non‐rodent mammals2019

    • Author(s)
      Matsuda Fuko、Ohkura Satoshi、Magata Fumie、Munetomo Arisa、Chen Jing、Sato Marimo、Inoue Naoko、Uenoyama Yoshihisa、Tsukamura Hiroko
    • Journal Title

      Journal of Obstetrics and Gynaecology Research

      Volume: 45 Issue: 12 Pages: 2318-2329

    • DOI

      10.1111/jog.14124

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Neonatal Estrogen Causes Irreversible Male Infertility via Specific Suppressive Action on Hypothalamic Kiss1 Neurons2019

    • Author(s)
      Minabe Shiori、Sato Marimo、Inoue Naoko、Watanabe Youki、Magata Fumie、Matsuda Fuko、Uenoyama Yoshihisa、Ozawa Hitoshi、Tsukamura Hiroko
    • Journal Title

      Endocrinology

      Volume: 160 Issue: 5 Pages: 1223-1233

    • DOI

      10.1210/en.2018-00732

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Central mechanism controlling pubertal onset in mammals: a triggering role of kisspeptin.2019

    • Author(s)
      Uenoyama Y, Inoue N, Nakamura S, Tsukamura H.
    • Journal Title

      Front Endocrinol

      Volume: 10 Pages: 312-312

    • DOI

      10.3389/fendo.2019.00312

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] エストロジェンが雌ラット視床下部ダイノルフィンニューロンの活性化に及ぼす影響2022

    • Author(s)
      藪下 怜也,Safiullah HAZIM,束村 博子,上野山 賀久,井上 直子
    • Organizer
      第115回 日本繁殖生物学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] ATP-P2X2 receptor signaling is essential for the generation of GnRH/LH surgevia activation of kisspeptin neurons in the anteroventral periventricular nucleus2022

    • Author(s)
      Hazim Safiullah, Ryoya Yabushita, Mayuko Nagae, Masumi Hirabayashi, Yoshihisa Uenoyama, Hiroko Tsukamura, Naoko Inoue
    • Organizer
      第48回日本神経内分泌学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Kiss1細胞常時可視化遺伝子改変ラットを用いた雌雄脳内Kiss1細胞分布の経時的解析2022

    • Author(s)
      山田晃熙、長江麻佑子、眞野哲也、井上直子、上野山賀久、平林真澄、束村博子
    • Organizer
      第26回日本生殖内分泌学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ATP-プリン受容体シグナリングによるマウスキスペプチンニューロン不死化細胞株活性化の検討2021

    • Author(s)
      井上直子、土肥由莉、上野山賀久、 束村博子
    • Organizer
      第94回日本内分泌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Search for purinergic neurons projecting to the vicinity of the kisspeptin neurons in the anteroventral periventricular nucleus by retrograde tracing2021

    • Author(s)
      Safiullah HAZIM, Yoshihisa UENOYAMA, Hiroko TSUKAMURA, Naoko INOUE
    • Organizer
      第114回日本繁殖生物学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] GnRH パルスジェネレーター解析のための新規 Cre 発現ラットの作製2021

    • Author(s)
      長江麻佑子、小林俊寛、三宝誠、平林真澄、水野直彬、中内啓光、榎本悠希、井上直子、束村博子、上野山賀久
    • Organizer
      第114回日本繁殖生物学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ATP-プリン受容体シグナリングによるLHサージ制御機構~ATPはキスペプチンニューロン不死化細胞のCa2+を上昇させる~2020

    • Author(s)
      土肥由莉、大塚裕記、上野山賀久、束村博子、井上直子
    • Organizer
      東海畜産学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ATP-プリン受容体シグナリングによるAVPVキスペプチンニューロン由来不死化細胞株活性化の検討2020

    • Author(s)
      土肥由莉、上野山賀久、束村博子、井上直子
    • Organizer
      第113回日本繁殖生物学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 遺伝子改変ラットを用いた卵胞発育中枢の同定2020

    • Author(s)
      長江麻佑子、上野山賀久、井上直子、小林憲太、平林真澄、束村博子
    • Organizer
      第10回名古屋大学医学系研究科・生理学研究所合同シンポジウム
    • Related Report
      2020 Annual Research Report
  • [Presentation] 排卵中枢キスペプチンニューロンを上位から制御するATP-プリン受容体シグナリングの役割2020

    • Author(s)
      井上直子、土田仁美、山田晃熙、土肥由莉、上野山賀久、束村博子
    • Organizer
      第24回日本生殖内分泌学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 哺乳類の排卵を制御する脳内メカニズム2019

    • Author(s)
      井上直子、上野山賀久、束村博子
    • Organizer
      第46回日本神経内分泌学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Remarks] 世界初!哺乳類の排卵を引き起こす脳内の仕組みを解明

    • URL

      https://www.nagoya-u.ac.jp/researchinfo/result/2023/03/post-466.html

    • Related Report
      2022 Annual Research Report

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Published: 2019-04-18   Modified: 2024-01-30  

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