下垂体後葉ホルモンの新たな生理作用〜遺伝子改変動物を用いた研究
下垂体後葉ホルモンであるバソプレシン・オキシトシ ンは、視床下部室傍核・視索上核の大細胞性神経分泌 ニューロンで産生され、下垂体後葉に投射した神経終末から活動電位依存性に循環血液中に開口分泌される。それぞれの受容体(V1a,b,V2およびOTR)は7回膜貫通型受容体であり、Gタンパクと共役している。バソプレシンは、V1a受容体を介して血管収縮、V1b受容体を介して下垂体前葉からのACTH分泌、腎臓のV2受容体を介して水の再吸収(抗利尿)を引き起こす。一方、オキシトシンは、OTRを介して妊娠末期の子宮筋の収縮・分娩 の促進、授乳期の乳腺平滑筋の収縮(射乳)を引き起こす。最近、バソプレシン・オキシ...
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Published in | 血管 Vol. 46; no. 3; pp. 1 - 6 |
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Main Authors | , |
Format | Journal Article |
Language | Japanese |
Published |
日本心脈管作動物質学会
26.11.2023
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Online Access | Get full text |
ISSN | 0911-4637 2759-2286 |
DOI | 10.60370/jjcircres.46.3_1 |
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Abstract | 下垂体後葉ホルモンであるバソプレシン・オキシトシ ンは、視床下部室傍核・視索上核の大細胞性神経分泌 ニューロンで産生され、下垂体後葉に投射した神経終末から活動電位依存性に循環血液中に開口分泌される。それぞれの受容体(V1a,b,V2およびOTR)は7回膜貫通型受容体であり、Gタンパクと共役している。バソプレシンは、V1a受容体を介して血管収縮、V1b受容体を介して下垂体前葉からのACTH分泌、腎臓のV2受容体を介して水の再吸収(抗利尿)を引き起こす。一方、オキシトシンは、OTRを介して妊娠末期の子宮筋の収縮・分娩 の促進、授乳期の乳腺平滑筋の収縮(射乳)を引き起こす。最近、バソプレシン・オキシトシン受容体が脳内にも広範に分布しており、概日リズム、愛情などの中枢作用にも関与することが注目されている。 私たちは、バソプレシン・オキシトシンを産生する神経分泌ニューロンを生細胞のまま同定するために蛍光タンパク遺伝子を挿入した融合遺伝子を用いてトランスジェニックラットを作出した。また、それぞれのニューロンを特異的に活性化するためにDREADDsを応用したトランスジェニックラットも作出した。本稿では、これらのトランスジェニックラットを用いて得られた新知見を概説する。 |
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AbstractList | 下垂体後葉ホルモンであるバソプレシン・オキシトシ ンは、視床下部室傍核・視索上核の大細胞性神経分泌 ニューロンで産生され、下垂体後葉に投射した神経終末から活動電位依存性に循環血液中に開口分泌される。それぞれの受容体(V1a,b,V2およびOTR)は7回膜貫通型受容体であり、Gタンパクと共役している。バソプレシンは、V1a受容体を介して血管収縮、V1b受容体を介して下垂体前葉からのACTH分泌、腎臓のV2受容体を介して水の再吸収(抗利尿)を引き起こす。一方、オキシトシンは、OTRを介して妊娠末期の子宮筋の収縮・分娩 の促進、授乳期の乳腺平滑筋の収縮(射乳)を引き起こす。最近、バソプレシン・オキシトシン受容体が脳内にも広範に分布しており、概日リズム、愛情などの中枢作用にも関与することが注目されている。 私たちは、バソプレシン・オキシトシンを産生する神経分泌ニューロンを生細胞のまま同定するために蛍光タンパク遺伝子を挿入した融合遺伝子を用いてトランスジェニックラットを作出した。また、それぞれのニューロンを特異的に活性化するためにDREADDsを応用したトランスジェニックラットも作出した。本稿では、これらのトランスジェニックラットを用いて得られた新知見を概説する。 |
Author | 丸山, 崇 上田, 陽一 |
Author_xml | – sequence: 1 fullname: 上田, 陽一 organization: 産業医科大学学長研究室 – sequence: 1 fullname: 丸山, 崇 organization: 産業医科大学医学部第1生理学 |
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ContentType | Journal Article |
Copyright | 2023 日本心脈管作動物質学会 |
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Chemogenetic Activation of Oxytocin Neurons Improves Pain in a Reserpine-induced Fibromyalgia Rat Model. Neuroscience. 2023;528:37-53. doi: 10.1016/j.neuroscience.2023.07.028. Katoh A, Fujihara H, Ohbuchi T, Onaka T, Hashimoto T, Kawata M, Suzuki H, Ueta Y. Highly visible expression of an oxytocin-monomeric red fluorescent protein 1 fusion gene in the hypothalamus and posterior pituitary of transgenic rats. Endocrinology. 2011;152(7):2768-2774. Ohbuchi T, Sato K, Suzuki H, Okada Y, DayanithiG, Murphy D, Ueta Y. Acid-sensing ion channels in rat hypothalamic vasopressin neurons of the supraoptic nucleus. Journal of Physiology 2010;588 (Pt12):2147-2162. Koshimizu TA, Nakamura K, Egashira N, Hiroyama M, Nonoguchi H, Tanoue A. Vasopressin V1a and V1b receptors: from molecules to physiological systems. Physiological Reviews. 2012;92(4): 1813-1864. Matsuura T, Kawasaki M, Hashimoto H, Yoshimura M, Motojima Y, Saito R, Ueno H, Maruyama T, Ishikura T, Sabanai K, Mori T, Ohnishi H, Onaka T, Sakai A, Ueta Y. Possible Involvement of the Rat Hypothalamo-Neurohypophysial/-Spinal Oxytocinergic Pathways in Acute Nociceptive Responses. Journal of Neuroendocrinology 2016;28 (6).doi: 10.1111/jne.12396. Ueta Y. Transgenic approaches to opening up new fields of vasopressin and oxytocin research. Journal of Neuroendocrinology. 2021;33(11):e13055. doi: 10.1111/jne.13055. Armstrong WE, Foehring RC, Kirchner MK, Sladek CD. Electrophysiological properties of identified oxytocin and vasopressin neurons. Journal of Neuroendocrinology. 2019;31(3):e12666. Ueta Y, Dayanithi G, Fujihara H. Hypothalamic vasopressin response to stress and various physiological stimuli:visualization in transgenic animal models. Hormone and Behavior 2011;59(2):221-226. Sanada K, Ueno H, Miyamoto T, Baba K, Tanaka K, Nishimura H, Nishimura K, Sonoda S, Yoshimura M, Maruyama T, Onaka T, Otsuji Y, Kataoka M, Ueta Y. AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats. American Journal of Physiology(Regul Integr Comp Physiol.)2022;322(3):R161-R169. Rigney N, de Vries GJ, Petrulis A, Young LJ. Oxytocin, Vasopressin, and Social Behavior: From Neuronal Circuits to Clinical Opportunities. Endocrinology 2022;163:1-13. Yamashita H, Inenaga K, Kawata M, Sano Y. Phasically firing neurons in the supraoptic nucleus of the rat hypothalamus: immunocytochemical and electrophysiological studies. Neuroscience Letters 1983;37(1):87-92. Fujio T, Fujihara H, Shibata M, Yamada S, Onaka T, Tanaka K, Morita H, Dayanithi G, Kawata M, Murphy D, Ueta Y. Exaggerated response of arginine vasopressin-enhanced green fluorescent protein fusion gene to salt loading without disturbance of body fluid homeostasis in rats. Journal of Neuroendocrinology 2006;18(10):776 -785. Iwanaga M, Ohno M, Katoh A, Ohbuchi T, Ishikura T, Fujihara H, Nomura M, Hachisuka K, Ueta Y. Upregulation of arginine vasopressin synthesis in the rat hypothalamus after kainic acid-induced seizures. Brain Research 2011;1424:1-8. Koizumi K, Yamashita H. Studies of antidromically identified neurosecretory cells of the hypothalamus by intracellular and extracellular recordings. Journal of Physiology 1972;221(3):683-705. Dayanithi G, Forostyak O, Forostyak S, Kayano T, Ueta Y, Verkhratsky A. Vasopressin and oxytocin in sensory neurones:expression, exocytotic release and regulation by lactation. Scientific Reports 2018;8(1):13084. Sanada K, Yoshimura M, Ikeda N, Baba K, Nishimura H, Nishimura K, Nonaka Y, Maruyama T, Miyamoto T, Mori M, Conway-Campbell B, Lightman S, Kataoka M, Ueta Y. Chemogenetic activation of endogenous arginine vasopressin exerts anorexigenic effects via central nesfatin-1/ NucB2 pathway. Journal of Physiological Sciences 2021;71(1):18. doi:10.1186/s12576-021-00802 -4. Kortus S, Srinivasan C, Forostyak O, Ueta Y, Sykova E, Chvatal A, Zapotocky M, Verkhratsky A, Dayanithi G. Physiology of spontaneous[Ca (2+)]i oscillations in the isolated vasopressin and oxytocin neurones of the rat supraoptic nucleus. Cell Calcium. 2016;59(6):280-288. Ohkubo J, Ohbuchi T, Yoshimura M, Maruyama T, Hashimoto H, Matsuura T, Suzuki H, Ueta Y. Differences in acid-induced currents between oxytocin-mRFP1 and vasopressin-eGFP neurons isolated from the supraoptic and paraventricular nuclei of transgenic rats. Neuroscience Letters. 2014;583:1-5. Matsuura T, Kawasaki M, Hashimoto H, Ishikura T, Yoshimura M, Ohkubo JI, Maruyama T, Motojima Y, Sabanai K, Mori T, Ohnishi H, Sakai A, Ueta Y. Fluorescent Visualisation of Oxytocin in the Hypothalamo-neurohypophysial/-spinal Pathways After Chronic Inflammation in Oxytocin- Monomeric Red Fluorescent Protein 1 Transgenic Rats. J Neuroendocrinol. 2015;27(7):636-46. doi: 10.1111/jne.12290. Baba K, Kawasaki M, Nishimura H, Suzuki H, Matsuura T, Ikeda N, Fujitani T, Yamanaka Y, Tsukamoto M, Ohnishi H, Yoshimura M, Maruyama T, Sanada K, Sonoda S, Nishimura K, Tanaka K, Onaka T, Ueta Y, Sakai A. Upregulation of the hypothalamo-neurohypophysial system and activation of vasopressin neurones attenuates hyperalgesia in a neuropathic pain model rat. Scientific Reports 2022;12(1):13046. doi:10.1038/s41598-022-17477-5. Nishimura H, Yoshimura M, Shimizu M, Sanada K,Sonoda S, Nishimura K, Baba K, Ikeda N, Motojima Y, Maruyama T, Nonaka Y, Baba R, Onaka T, Horishita T, Morimoto H, Yoshida Y, Kawasaki M, Sakai A, Muratani M, Conway-Campbell B, Lightman S, Ueta Y. Endogenous oxytocin exerts anti-nociceptive and anti-inflammatory effects in rats. Communications Biology 2022;5(1):907. doi:10.1038/s42003-022-03879-8. Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nature Review Neuroscience 2011;12(9):524- 538. Suzuki H, Kawasaki M, Ohnishi H, Nakamura T, Ueta Y. Regulatory mechanism of the arginine vasopressin-enhanced green fluorescent protein fusion gene expression in acute and chronic stress.Peptides. 2009;30(9):1763-1770. Sharma K, Haque M, Guidry R, Ueta Y, Teruyama R. Effect of dietary salt intake on epithelial Na+ channels(ENaC)in vasopressin magnocellular neurosecretory neurons in the rat supraoptic nucleus. Journal of Physiology 2017;595(17):5857 -5874. Nishimura K, Yoshino K, Ikeda N, Baba K, Sanada K, Akiyama Y, Nishimura H, Tanaka K, Sonoda S, Ueno H, Yoshimura M, Maruyama T, Hachisuga T, Ueta Y. Oestrogen-dependent hypothalamic oxytocin expression with changes in feeding and body weight in female rats. Communications Biology. 2022;5(1):912. doi: 10.1038/s42003- 022-03889-6 Ueta Y, Kannan H, Higuchi T, Negoro H, Yamashita H. CCK-8 excites oxytocin-secreting neurons in the paraventricular nucleus in rats-possible involvement of noradrenergic pathway. Brain Research Bulletin 1993;32(5):453-459. Maruyama T, Ohbuchi T, Fujihara H, Shibata M, Mori K, Murphy D, Dayanithi G, Ueta Y. Diurnal changes of arginine vasopressin-enhanced green fluorescent protein fusion transgene expression in the rat suprachiasmatic nucleus. Peptides. 2010;31 (11):2089-2093. Jurek B, Neumann ID. The Oxytocin Receptor: From Intracellular Signaling to Behavior. Physiological Reviews. 2018;98(3):1805-1908. Brownstein MJ, Russell JT, Gainer H. Synthesis, transport, and release of posterior pituitary hormones. Science 1980;207(4429):373-378. Young WS 3rd, Gainer H. Transgenesis and the study of expression, cellular targeting and function of oxytocin, vasopressin and their receptors. Neuroendocrinology 2003;78:185-203. |
References_xml | – reference: Suzuki H, Kawasaki M, Ohnishi H, Nakamura T, Ueta Y. Regulatory mechanism of the arginine vasopressin-enhanced green fluorescent protein fusion gene expression in acute and chronic stress.Peptides. 2009;30(9):1763-1770. – reference: Baba K, Kawasaki M, Nishimura H, Suzuki H, Matsuura T, Ikeda N, Fujitani T, Yamanaka Y, Tsukamoto M, Ohnishi H, Yoshimura M, Maruyama T, Sanada K, Sonoda S, Nishimura K, Tanaka K, Onaka T, Ueta Y, Sakai A. Upregulation of the hypothalamo-neurohypophysial system and activation of vasopressin neurones attenuates hyperalgesia in a neuropathic pain model rat. Scientific Reports 2022;12(1):13046. doi:10.1038/s41598-022-17477-5. – reference: Brownstein MJ, Russell JT, Gainer H. Synthesis, transport, and release of posterior pituitary hormones. Science 1980;207(4429):373-378. – reference: Jurek B, Neumann ID. The Oxytocin Receptor: From Intracellular Signaling to Behavior. Physiological Reviews. 2018;98(3):1805-1908. – reference: Maruyama T, Ohbuchi T, Fujihara H, Shibata M, Mori K, Murphy D, Dayanithi G, Ueta Y. Diurnal changes of arginine vasopressin-enhanced green fluorescent protein fusion transgene expression in the rat suprachiasmatic nucleus. Peptides. 2010;31 (11):2089-2093. – reference: Matsuura T, Kawasaki M, Hashimoto H, Yoshimura M, Motojima Y, Saito R, Ueno H, Maruyama T, Ishikura T, Sabanai K, Mori T, Ohnishi H, Onaka T, Sakai A, Ueta Y. Possible Involvement of the Rat Hypothalamo-Neurohypophysial/-Spinal Oxytocinergic Pathways in Acute Nociceptive Responses. Journal of Neuroendocrinology 2016;28 (6).doi: 10.1111/jne.12396. – reference: Ueta Y, Kannan H, Higuchi T, Negoro H, Yamashita H. CCK-8 excites oxytocin-secreting neurons in the paraventricular nucleus in rats-possible involvement of noradrenergic pathway. Brain Research Bulletin 1993;32(5):453-459. – reference: Nishimura K, Yoshino K, Ikeda N, Baba K, Sanada K, Akiyama Y, Nishimura H, Tanaka K, Sonoda S, Ueno H, Yoshimura M, Maruyama T, Hachisuga T, Ueta Y. Oestrogen-dependent hypothalamic oxytocin expression with changes in feeding and body weight in female rats. Communications Biology. 2022;5(1):912. doi: 10.1038/s42003- 022-03889-6 – reference: Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nature Review Neuroscience 2011;12(9):524- 538. – reference: Yamashita H, Inenaga K, Kawata M, Sano Y. Phasically firing neurons in the supraoptic nucleus of the rat hypothalamus: immunocytochemical and electrophysiological studies. Neuroscience Letters 1983;37(1):87-92. – reference: Ueta Y. Transgenic approaches to opening up new fields of vasopressin and oxytocin research. Journal of Neuroendocrinology. 2021;33(11):e13055. doi: 10.1111/jne.13055. – reference: Dayanithi G, Forostyak O, Forostyak S, Kayano T, Ueta Y, Verkhratsky A. Vasopressin and oxytocin in sensory neurones:expression, exocytotic release and regulation by lactation. Scientific Reports 2018;8(1):13084. – reference: Fujio T, Fujihara H, Shibata M, Yamada S, Onaka T, Tanaka K, Morita H, Dayanithi G, Kawata M, Murphy D, Ueta Y. Exaggerated response of arginine vasopressin-enhanced green fluorescent protein fusion gene to salt loading without disturbance of body fluid homeostasis in rats. Journal of Neuroendocrinology 2006;18(10):776 -785. – reference: Matsuura T, Kawasaki M, Hashimoto H, Ishikura T, Yoshimura M, Ohkubo JI, Maruyama T, Motojima Y, Sabanai K, Mori T, Ohnishi H, Sakai A, Ueta Y. Fluorescent Visualisation of Oxytocin in the Hypothalamo-neurohypophysial/-spinal Pathways After Chronic Inflammation in Oxytocin- Monomeric Red Fluorescent Protein 1 Transgenic Rats. J Neuroendocrinol. 2015;27(7):636-46. doi: 10.1111/jne.12290. – reference: Koizumi K, Yamashita H. Studies of antidromically identified neurosecretory cells of the hypothalamus by intracellular and extracellular recordings. Journal of Physiology 1972;221(3):683-705. – reference: Ohbuchi T, Sato K, Suzuki H, Okada Y, DayanithiG, Murphy D, Ueta Y. Acid-sensing ion channels in rat hypothalamic vasopressin neurons of the supraoptic nucleus. Journal of Physiology 2010;588 (Pt12):2147-2162. – reference: Kortus S, Srinivasan C, Forostyak O, Ueta Y, Sykova E, Chvatal A, Zapotocky M, Verkhratsky A, Dayanithi G. Physiology of spontaneous[Ca (2+)]i oscillations in the isolated vasopressin and oxytocin neurones of the rat supraoptic nucleus. Cell Calcium. 2016;59(6):280-288. – reference: Ueta Y, Dayanithi G, Fujihara H. Hypothalamic vasopressin response to stress and various physiological stimuli:visualization in transgenic animal models. Hormone and Behavior 2011;59(2):221-226. – reference: Sharma K, Haque M, Guidry R, Ueta Y, Teruyama R. Effect of dietary salt intake on epithelial Na+ channels(ENaC)in vasopressin magnocellular neurosecretory neurons in the rat supraoptic nucleus. Journal of Physiology 2017;595(17):5857 -5874. – reference: Young WS 3rd, Gainer H. Transgenesis and the study of expression, cellular targeting and function of oxytocin, vasopressin and their receptors. Neuroendocrinology 2003;78:185-203. – reference: Nishimura H, Yoshimura M, Shimizu M, Sanada K,Sonoda S, Nishimura K, Baba K, Ikeda N, Motojima Y, Maruyama T, Nonaka Y, Baba R, Onaka T, Horishita T, Morimoto H, Yoshida Y, Kawasaki M, Sakai A, Muratani M, Conway-Campbell B, Lightman S, Ueta Y. Endogenous oxytocin exerts anti-nociceptive and anti-inflammatory effects in rats. Communications Biology 2022;5(1):907. doi:10.1038/s42003-022-03879-8. – reference: Ikeda N, Kawasaki M, Baba K, Nishimura H, Fujitani T, Suzuki H, Matsuura T, Ohnishi H, Shimizu M, Sanada K, Nishimura K, Yoshimura M, Maruyama T, Conway-Campbell BL, Onaka T, Teranishi H, Hanada R, Ueta Y, Sakai A. Chemogenetic Activation of Oxytocin Neurons Improves Pain in a Reserpine-induced Fibromyalgia Rat Model. Neuroscience. 2023;528:37-53. doi: 10.1016/j.neuroscience.2023.07.028. – reference: Ohkubo J, Ohbuchi T, Yoshimura M, Maruyama T, Hashimoto H, Matsuura T, Suzuki H, Ueta Y. Differences in acid-induced currents between oxytocin-mRFP1 and vasopressin-eGFP neurons isolated from the supraoptic and paraventricular nuclei of transgenic rats. Neuroscience Letters. 2014;583:1-5. – reference: Sanada K, Ueno H, Miyamoto T, Baba K, Tanaka K, Nishimura H, Nishimura K, Sonoda S, Yoshimura M, Maruyama T, Onaka T, Otsuji Y, Kataoka M, Ueta Y. AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats. American Journal of Physiology(Regul Integr Comp Physiol.)2022;322(3):R161-R169. – reference: Katoh A, Fujihara H, Ohbuchi T, Onaka T, Hashimoto T, Kawata M, Suzuki H, Ueta Y. Highly visible expression of an oxytocin-monomeric red fluorescent protein 1 fusion gene in the hypothalamus and posterior pituitary of transgenic rats. Endocrinology. 2011;152(7):2768-2774. – reference: Rigney N, de Vries GJ, Petrulis A, Young LJ. Oxytocin, Vasopressin, and Social Behavior: From Neuronal Circuits to Clinical Opportunities. Endocrinology 2022;163:1-13. – reference: Armstrong WE, Foehring RC, Kirchner MK, Sladek CD. Electrophysiological properties of identified oxytocin and vasopressin neurons. Journal of Neuroendocrinology. 2019;31(3):e12666. – reference: Ohkubo J, Ohbuchi T, Yoshimura M, Maruyama T, Ishikura T, Matsuura T, Suzuki H, Ueta Y. Electrophysiological effects of kainic acid on vasopressin-enhanced green fluorescent protein and oxytocin-monomeric red fluorescent protein 1 neurones isolated from the supraoptic nucleus in transgenic rats. Journal of Neuroendocrinology 2014;26(1):43-51. – reference: Iwanaga M, Ohno M, Katoh A, Ohbuchi T, Ishikura T, Fujihara H, Nomura M, Hachisuka K, Ueta Y. Upregulation of arginine vasopressin synthesis in the rat hypothalamus after kainic acid-induced seizures. Brain Research 2011;1424:1-8. – reference: Koshimizu TA, Nakamura K, Egashira N, Hiroyama M, Nonoguchi H, Tanoue A. Vasopressin V1a and V1b receptors: from molecules to physiological systems. Physiological Reviews. 2012;92(4): 1813-1864. – reference: Ueta Y, Fujihara H, Serino R, Dayanithi G, Ozawa H, Matsuda K, Kawata M, Yamada J, Ueno S, Fukuda A, Murphy D. 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Snippet | 下垂体後葉ホルモンであるバソプレシン・オキシトシ ンは、視床下部室傍核・視索上核の大細胞性神経分泌 ニューロンで産生され、下垂体後葉に投射した神経終末から活動電位... |
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Title | 下垂体後葉ホルモンの新たな生理作用〜遺伝子改変動物を用いた研究 |
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