Functional analysis of the metabotropic glutamate receptor and the acid-sensitive ion channels as a urine collection control molecule

• Project/Area Number: 16K11042
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: University of Yamanashi
• Principal Investigator: YOSHIYAMA Mitsuharu 山梨大学, 大学院総合研究部, 医学研究員 (20422694)
• Research Collaborator: IHARA Tatsuya
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: マウス / 代謝型グルタミン酸受容体 / 酸感受性イオンチャンネル / 下部尿路機能 / 膀胱 / 尿道 / 中枢神経 / 末梢神経 / 酸感受性チャネル / 膀胱過活動 / 求心路 / 蓄尿障害 / 外尿道括約筋 / 興奮性グルタミン酸受容体 / 酸感受性イオンチャネル / 排尿機能学

Outline of Final Research Achievements

The study using metabotropic glutamate receptor subtype 1 (mGluR1) gene deficit (KO) mice and mGluR5 antagonist revealed that mGluR1 and mGluR5 are involved in excitatory afferent signal transmission from the bladder in control of lower urinary tract (LUT) function and that the mGluR phenotype has a sex difference in the LUT function. Moreover, another study showed that acid-sensing ion channels (ASICs) are associated with excitatory afferent signal transduction in acid-induced bladder hyperreflexia as well as normal bladder activity. The present studies show that mGluR1, mGluR5 and ASICs can be target molecules for development of pharmacotherapy of lower urinary tract dysfunction such as bladder overactivity and thus these results would contribute to ameliorating a quality of life of patients who suffer from such dysfunction and to improving social productivity.

Academic Significance and Societal Importance of the Research Achievements

膀胱過活動症状はヒトの日常生活の質と生産活動性を著しく低下させる。故に、その発症機構の解明と治療法の開発は、同症状による損失を回避する上で重要である。本研究は、膀胱からの興奮性求心性信号伝達に代謝型グルタミン酸受容体(mGluR)と酸感受性イオンチャネル(ASICs)が関与することを解明した。一方、このmGluR関与の程度には雌雄差があることも明らかにした。この結果は、標的分子の表現型に性差がある可能性を念頭に研究を実施するべきであることを示唆する。近年、医学研究において、遺伝子関連の表現型や薬物療法への反応性に性別を考慮することの重要性が提唱されており、本研究結果はそれに同調する。

Research Products

• [Int'l Joint Research] Ohio State University/University of Vermont/University of Pittsburgh(米国)
• [Int'l Joint Research] McGill University(カナダ)
• [Int'l Joint Research] University of Kahramanmaras/University of Cukurova(トルコ)
• [Int'l Joint Research] University of Pittsburgh/Ohio State University/University of Vermont(U.S.A.)
• [Int'l Joint Research] McGill University(Canada)
• [Int'l Joint Research] University of Pittsburgh/Wake Forest University(米国)
• [Int'l Joint Research] UROsphere S.A.S.(フランス)
• [Int'l Joint Research] Helsinn Healthcare S.A.(スイス)
• [Int'l Joint Research] Yonsei University(韓国)
• [Journal Article] The effect of Ferula elaeochytris root extract on erectile dysfunction in streptozotocin-induced diabetic rat (2019)
  • Author(s): Eser Nadire、Buyuknacar Hacer Sinem、Cimentepe Ozge Ozturk、Gocmen Cemil、Ucar Yilmaz、Erdogan Seyda、Yoshiyama Mitsuharu
  • Journal Title: International Journal of Impotence Research Volume: 印刷中 Issue: 2 Pages: 186-194
  • DOI: 10.1038/s41443-019-0137-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The oscillation of intracellular Ca2+ influx associated with the circadian expression of Piezo1 and TRPV4 in the bladder urothelium (2018)
  • Author(s): Ihara Tatsuya、Mitsui Takahiko、Nakamura Yuki、Kanda Mie、Tsuchiya Sachiko、Kira Satoru、Nakagomi Hiroshi、Sawada Norifumi、Kamiyama Manabu、Hirayama Yuri、Shigetomi Eiji、Shinozaki Youichi、Yoshiyama Mitsuharu、Nakao Atsuhito、Takeda Masayuki、Koizumi Schuichi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5699-5699
  • DOI: 10.1038/s41598-018-23115-w
  • Peer Reviewed / Open Access
• [Journal Article] Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury (2018)
  • Author(s): Ryu Jae Cheon、Tooke Katharine、Malley Susan E.、Soulas Anastasia、Weiss Tirzah、Ganesh Nisha、Saidi Nabila、Daugherty Stephanie、Saragovi Uri、Ikeda Youko、Zabbarova Irina、Kanai Anthony J.、Yoshiyama Mitsuharu、Farhadi H. Francis、de Groat William C.、Vizzard Margaret A.、Yoon Sung Ok
  • Journal Title: Journal of Clinical Investigation Volume: 128 Issue: 5 Pages: 1772-1786
  • DOI: 10.1172/jci97837
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The time-dependent variation of ATP release in mouse primary cultured urothelial cells is regulated by the Clock gene. (2018)
  • Author(s): Ihara T, Mitsui T, Nakamura Y, Kanda M, Tsuchiya S, Kira S, Nakagomi H, Sawada N, Kamiyama M, Hirayama Y, Shigetomi E, Shinozaki Y, Yoshiyama M, Nakao A, Takeda M Koizumi S
  • Journal Title: Neurourology and urodynamics Volume: 37 Issue: 8 Pages: 2535-2543
  • DOI: 10.1002/nau.23793
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Circadian expression of Piezo1, TRPV4, Connexin26, and VNUT, associated with the expression levels of the clock genes in mouse primary cultured urothelial cells (2017)
  • Author(s): Ihara Tatsuya、Mitsui Takahiko、Nakamura Yuki、Kanda Mie、Tsuchiya Sachiko、Kira Satoru、Nakagomi Hiroshi、Sawada Norifumi、Hirayama Yuri、Shibata Keisuke、Shigetomi Eiji、Shinozaki Yoichi、Yoshiyama Mitsuharu、Nakao Atsuhito、Takeda Masayuki、Koizumi Schuichi
  • Journal Title: Neurourology and Urodynamics Volume: 37 Issue: 3 Pages: 942-951
  • DOI: 10.1002/nau.23400
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] P2Y6-deficiency increases micturition frequency and attenuates sustained contractility of the urinary bladder in mice (2017)
  • Author(s): Kira S,Yoshiyama M,Tsuchiya S,Shigetomi E,Miyamoto T,Nakagomi H,Shibata K,Mochizuki T,Takeda M,Koizumi S
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 771-771
  • DOI: 10.1038/s41598-017-00824-2
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The role of capsaicin-sensitive C-fiber afferent pathways in the control of micturition in spinal-intact and spinal cord-injured mice (2017)
  • Author(s): Kadekawa Katsumi、Majima Tsuyoshi、Shimizu Takahiro、Wada Naoki、de Groat William C.、Kanai Anthony J.、Goto Momokazu、Yoshiyama Mitsuharu、Sugaya Kimio、Yoshimura Naoki
  • Journal Title: Ａｍｅｒｉｃａｎ Ｊｏｕｒｎａｌ ｏｆ Ｐｈｙｓｉｏｌｏｇｙ Ｒｅｎａｌ Ｐｈｙｓｉｏｌｏｇｙ Volume: 313 Issue: 3 Pages: F796-F804
  • DOI: 10.1152/ajprenal.00097.2017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clock Genes Regulate the Circadian Expression of Piezo1, TRPV4, Connexin26, and VNUT in an Ex Vivo Mouse Bladder Mucosa. (2017)
  • Author(s): 5.Ihara T, Mitsui T, Nakamura Y, Kira S, Nakagomi H, Sawada N, Hirayama Y, Shibata K, Shigetomi E, Shinozaki Y, Yoshiyama M, Andersson KE, Nakao A, Takeda M, Koizumi S
  • Journal Title: PLoS One Volume: 12 Issue: 1 Pages: e0168234-e0168234
  • DOI: 10.1371/journal.pone.0168234
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ketanserin and naftopidil enhance the potentiating effect of alpha-methyl-serotonin on the neurally-induced contraction of human isolated urinary bladder muscle strips (2017)
  • Author(s): Hattori T, Lluel P, Rouget C, Rekik M, Yoshiyama M
  • Journal Title: International Neurourology Journal Volume: 21 Issue: 1 Pages: 20-28
  • DOI: 10.5213/inj.1732758.379
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of bladder and external urethral activity in mice with or without spinal cord injury - a comparison study with rats (2016)
  • Author(s): Kadekawa K, Yoshimura N, Majima T, Wada N, Shimizu T, Birder LA, Kanai AJ, de Groat WC, Sugaya K, Yoshiyama M
  • Journal Title: American Journal of Physiology Regulatory Integrative Comparative Physiology Volume: 310 Issue: 8 Pages: R752-R758
  • DOI: 10.1152/ajpregu.00450.2015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Urothelial ATP exocytosis: regulation of bladder compliance in the urine storage phase (2016)
  • Author(s): Nakagomi H,Yoshiyama M,Mochizuki T,Miyamoto T,Komatsu R,Imura Y,Morizawa Y,Hiasa M,Kira S,Fujishita K,Shibata K,Shigetomi E,Shinozaki Y,Takeda M,Koizumi S
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 29761-29761
  • DOI: 10.1038/srep29761
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Netupitant, a potent and highly selective NK1 receptor antagonist, alleviates acetic acid-induced bladder overactivity in anesthetized guinea-pigs (2016)
  • Author(s): Palea S, Guilloteau V, Rekik M, Lovati E, Guerard M, Guardia MA, Lluel P, Pietra C, Yoshiyama M
  • Journal Title: Frontiers in Pharmacology Volume: 7
  • DOI: 10.3389/fphar.2016.00234
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Clock mutant mouse is a novel experimental model for nocturia and nocturnal polyuria. (2016)
  • Author(s): Ihara, T., Mitsui, T., Nakamura, Y., Kira, S., Miyamoto, T., Nakagomi, H., Sawada, N., Hirayama, Y., Shibata, K., Shigetomi, E., Shinozaki, Y., Yoshiyama, M., Nakao, A., *Takeda, M. *Koizumi, S.
  • Journal Title: Neurourology and Urodynamics Volume: 36 Issue: 4 Pages: 1034-1038
  • DOI: 10.1002/nau.23062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Metabotropic glutamate receptor subtypes 1 and 5 are necessary for synergic activity of bladder and external urethral sphincter in mice with spinal cord injury (2018)
  • Author(s): Yoshiyama Mitsuharu、Takeda Masayuki
  • Organizer: The 33rd Annual Congress of the European Association of Urology
  • Int'l Joint Research
• [Presentation] The sex influences metabotropic glutamate receptor subtype 1 phenotype in control of lower urinary tract activity (2018)
  • Author(s): Yoshiyama Mitsuharu、Mochizuki Tsutomu、Takeda Masayuki
  • Organizer: International Continence Society 48th Annual meeting
  • Int'l Joint Research
• [Presentation] マウス下部尿路機能制御において性別は代謝型グルタミン酸受容体サブタイプ１表現型へ有意に影響する (2018)
  • Author(s): 芳山充晴、望月勉、武田正之
  • Organizer: 第25回日本排尿機能学会
• [Presentation] Metabotropic glutamate receptor subtypes 1 and 5 are necessary for synergic activity of bladder and external urethral sphincter in mice with spinal cord injury (2018)
  • Author(s): M Yoshiyama, M Takeda
  • Organizer: European Association of Urology Annual congress
  • Int'l Joint Research
• [Presentation] Pelvic floor supportive underwear enhances alleviating effect of pelvic floor muscle training on lower urinary tract symptoms in pelvic organ prolapse patients (2017)
  • Author(s): T Taniguchi,Y Kobayashi,S Takaoka,H Kobayashi,T Mitsui,M Yoshiyama,M Takeda
  • Organizer: International Continence Society 47th Annual meeting,
  • Int'l Joint Research
• [Presentation] Effect of restraint stress on alternation of circadian bladder function to induce nocturia (2017)
  • Author(s): T Ihara,Y Nakamura,T Mitsui,Y Otake,Y Imai,S Kira,H Nakagomi,N Sawada,M Yoshiyama,S Koizumi,A Nakao,M Takeda
  • Organizer: International Continence Society 47th Annual meeting
  • Int'l Joint Research
• [Presentation] Blockade of metabotropic glutamatergic pathways worsens voiding dysfunction in mice with chronically-transected spinal cord (2017)
  • Author(s): M Yoshiyama,M Takeda
  • Organizer: International Continence Society 47th Annual meeting
  • Int'l Joint Research
• [Presentation] 代謝型グルタミン酸受容体経路遮断は完全脊髄損傷マウスの排尿機能不全を増悪する (2017)
  • Author(s): 芳山充晴、武田正之
  • Organizer: 第24回日本排尿機能学会
• [Presentation] Circadian regulations of Piezo1, TRPV4, Connexin26 and VNUT by clock genes in the mouse bladder urothelium (2016)
  • Author(s): Ihara T, Nakamura Y, Mitsui T, Kira S, Nakagomi H, Sawada N, Shinozaki Y, Yoshiyama M, Nakao A, Takeda M, Koizumi S
  • Organizer: International Continence Society 46th Annual meeting
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-09-15
  • Int'l Joint Research
• [Presentation] The role of capsaicin-sensitive C-fiber afferent pathways in the control of micturition in normal mice and lower urinary tract dysfunction in mice with spinal cord injury (2016)
  • Author(s): Kadekawa K, Yoshiyama M, Wada N, Shimizu T, Majima T, Tyagi P, Kanai A, de Groat W, Sugaya K, Yoshimura N
  • Organizer: International Continence Society 46th Annual meeting
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-09-14
  • Int'l Joint Research
• [Presentation] Evaluation of a novel underwear which supports the pelvic floor in pelvic organ prolapse patients (2016)
  • Author(s): Taniguchi T, Kobayashi Y, Kobayashi H, Mitsui T, Takaoka T, Yoshiyama M, Takeda M
  • Organizer: International Continence Society 46th Annual meeting
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-09-13
  • Int'l Joint Research
• [Presentation] Preclinical Urodynamics - Optimisation of Techniques, Measurements and Interpretation (2016)
  • Author(s): Yoshiyama M
  • Organizer: International Continence Society 46th Annual meeting
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-09-13
  • Int'l Joint Research
• [Presentation] Clock genes regulate circadian rhythm of VNUT expression,Connexin26 expression and stretch-evoked ATP release in the cultured urothelial cells (2016)
  • Author(s): Ihara T, Kira S, Miyamoto T, Sawada N, Nakagomi H, Mitsui T, Kobayashi H, Yoshiyama M, Takeda M, Nakamura Y, Nakao A, Shigetomi E, Shinozaki Y, Koizumi S
  • Organizer: American Urological Association Annual Meeting
  • Place of Presentation: San Diego, California, U.S.A.
  • Year and Date: 2016-05-09
  • Int'l Joint Research
• [Presentation] Glycine transporter type 2 (GlyT2) inhibitor ameliorates autonomic dysreflexia during bladder hydrodistention and detrusor overactivity in IC/BPS rat model (2016)
  • Author(s): Kim SW, Moon SY, Son HS, Yoshiyama M, Kim JH
  • Organizer: American Urological Association Annual Meeting
  • Place of Presentation: San Diego, California, U.S.A.
  • Year and Date: 2016-05-07
  • Int'l Joint Research
• [Presentation] Characterization of tonic activity of external urethral sphincter during voiding underlying inefficient voiding after spinal cord injury in rats (2016)
  • Author(s): Kadekawa K, Yoshiyama M, Majima T, Tyagi P, Sugaya K, Yoshimura N
  • Organizer: American Urological Association Annual Meeting
  • Place of Presentation: San Diego, California, U.S.A.
  • Year and Date: 2016-05-06
  • Int'l Joint Research
• [Book] Spinal cord, In: Neurourology: theory and practice (Eds. Limin Liao, Helmut Madersbacher) (2019)
  • Author(s): Yoshiyama Mitsuharu、Kakizaki Hidehiro
  • Total Pages: 583
  • Publisher: Springer, Dordrecht
  • ISBN: 9789401775090