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Motohiro Nishida Last modified date:2021.08.17

Graduate School
Undergraduate School

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Academic Degree
Country of degree conferring institution (Overseas)
Field of Specialization
Pharmacology, Physiology
ORCID(Open Researcher and Contributor ID)
Total Priod of education and research career in the foreign country
Outline Activities
Study on the intracellular signaling pathways regulating adaptation or maladaptation of the heart against physical stresses
Study on the regulation of cardiac redox homeostasis by reactive sulfur species
Study on the pathophysiological roles of receptor-activated TRPC channels in the heart
Drug discovery and evolution focusing on mitochondrial quality control

Pharmacology, Drug Disovery and Evolution

Social activities:
presentation in scientific meeting, lecturer on demand (high school), etc.
Research Interests
  • Green-Pharma Research focusing on the pathology-specific protein-protein interactions
    keyword : intractable disease, muscle atrophy, protein-protein interaction (PPI), drug development and repositioning
  • Role of receptor-activated TRP calcium channels in cardiocirculatory homeostasis
    keyword : cardiocirculatory homeostasis, TRPC channel, autonomic nervous system
  • Physiological role of supersulfides
    keyword : Supersulfides, muscles, mitochondria, repair and regeneration
Current and Past Project
  • Study on the development of quantitative imaging of supersulfides and elucidation of their physiological roles
Academic Activities
1. Nishida M, Sunggip C, Kitajima N & Kurose H, Angiotensin: New Research, Redox regulation of angiotensin receptor signaling in the heart., NOVA Publishers (New York), 2012.03.
2. Nishida M, Ohba M, Nakaya M & Kurose H., Heart Failure: Symptoms, Causes and Treatment Options, NOVA Publishers (New York), Edited by Wright MS. 51-72頁, 2011.03, Structural remodeling of the heart, including myocardial hypertrophy and fibrosis, is a key determinant for the clinical outcome of heart failure. A variety of evidence indicates the importance of neurohumoral factors, such as endothelin-1, angiotensin II, and norepinephrine for the initial phase of the development of cardiac remodeling. These agonists stimulate seven transmembrane spanning receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins) of the Gi, Gq and G12 subfamilies. The pathophysiological roles of each G protein-mediated signaling have been revealed by studies using transgenic and knockout mice. Using specific pharmacological tools to assess the involvement of G protein signaling pathways, we have found that diacylglycerol-activated transient receptor potential canonical (TRPC) channels (TRPC3 and TRPC6), one of the downstream effectors regulated by Gαq, work as a key mediator in the development of cardiac hypertrophy. In contrast, we also revealed that activation of Gα12 family proteins in cardiomyocytes mediates pressure overload-induced cardiac fibrosis. Stimulation of purinergic P2Y6 receptors by extracellular nucleotides released by mechanical stretch is a trigger of Gα12-mediated fibrotic responses of the heart. Although cardiac fibrosis is believed to accompany with Gαq-mediated pathological hypertrophy that eventually results in heart failure, our results clearly show that cardiac fibrosis and hypertrophy are independent processes. These findings will provide a new insight into the molecular mechanisms underlying pathogenesis of heart failure..
1. Nishida M, Kitajima N, Saiki S, Nakaya M & Kurose H, Regulation of angiotensin II receptor signaling by cysteine modification of NF-kB., Nitric Oxide, 2011.08.
2. Nishida M, Roles of heterotrimetric GTP-binding proteins in the progression of heart failure., J. Pharmacol. Sci., 2011.06.
3. Nishida M, Kurose H, Roles of TRP channels in the development of cardiac hypertrophy., Naunyn Schmiedebergs Arch Pharmacol. , Vol.378,395-406, 2008.07.
4. Nishida M, Hara Y, Yoshida T, Inoue R & Mori Y., TRP channels: formation of signal complex and regulation of cellular functions, Microcirculation, 13, 535-550, 2006.09.
5. Mori Y, Nishida M, Shimizu S, Ishii M, Yoshinaga T, Ino M, Sawada K & Niidome T, Mice lacking the a1B subunit (CaV 2.2) reveals a predominant role of N-type Ca2+ channels in the sympathetic regulation of circulatory system., Trends in Cardiovascular Medicine, 12, 270-275, 2002.12.
6. Nishida M. , Heterotrimetric G protein signaling in Heart Failure. , J. Pharmacol. Sci., in press..
1. Nishiyama K, Numaga-Tomita T, Fujimoto Y, Tanaka T, Toyama C, Nishimura A, Yamashita T, Matsunaga N, Koyanagi S, Azuma YT, Ibuki Y, Uchida K, Ohdo S, Nishida M, Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3-Nox2 protein complex, British Journal of Pharmacology, 10.1111/bph.14777, 176, 18, 3723-3738, 2019.09.
2. Nishimura A, Shimoda K, Tanaka T, Toyama T, Nishiyama K, Shinkai Y, Numaga-Tomita T, Yamazaki D, Kanda Y, Akaike T, Kumagai Y, Nishida M, Depolysulfidation of Drp1 induced by low-dose methylmercury exposure increases cardiac vulnerability to hemodynamic overload, Science Signaling, 10.1126/scisignal.aaw1920, 12, 587, pii: eaaw1920, Jun 25;12(587). pii: eaaw1920. doi: 10.1126/scisignal.aaw1920, 2019.06.
3. Shimauchi T, Numaga-Tomita T, Ito T, Nishimura A, Matsukane R, Oda S, Hoka S, Ide T, Koitabashi N, Uchida K, Sumimoto H, Mori Y, Nishida M, TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy, JCI Insight. Aug 3;2(15). pii: 93358 (2017). doi: 10.1172/jci.insight.93358., doi: 10.1172/jci.insight.93358., 2017.08, Myocardial atrophy is a wasting of cardiac muscle due to hemodynamic unloading. Doxorubicin is a highly effective anticancer agent but also induces myocardial atrophy through a largely unknown mechanism. Here, we demonstrate that inhibiting transient receptor potential canonical 3 (TRPC3) channels abolishes doxorubicin-induced myocardial atrophy in mice. Doxorubicin increased production of ROS in rodent cardiomyocytes through hypoxic stress–mediated upregulation of NADPH oxidase 2 (Nox2), which formed a stable complex with TRPC3. Cardiomyocyte-specific expression of TRPC3 C-terminal minipeptide inhibited TRPC3-Nox2 coupling and suppressed doxorubicin-induced reduction of myocardial cell size and left ventricular (LV) dysfunction, along with its upregulation of Nox2 and oxidative stress, without reducing hypoxic stress. Voluntary exercise, an effective treatment to prevent doxorubicin-induced cardiotoxicity, also downregulated the TRPC3-Nox2 complex and promoted volume load–induced LV compliance, as demonstrated in TRPC3-deficient hearts. These results illustrate the impact of TRPC3 on LV compliance and flexibility and, focusing on the TRPC3-Nox2 complex, provide a strategy for prevention of doxorubicin-induced cardiomyopathy..
4. 西田 基宏, The purinergic P2Y6 receptor heterodimerizes with the angiotensin AT1 receptor to promote angiotensin II-induced hypertension, Science Signaling, doi: 10.1126/scisignal.aac9187., Vol. 9, Issue 411, ra7, 2016.01, The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor (GPCR), promoted Ang II–induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II–induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein–dependent vascular hypertrophy but reduced β-arrestin–dependent AT1R internalization. Pharmacological disruption of AT1R-P2Y6R heterodimers by the P2Y6R antagonist MRS2578 suppressed Ang II–induced hypertension in mice. Furthermore, P2Y6R abundance increased with age in vascular smooth muscle cells. The increased abundance of P2Y6R converted AT1R-stimulated signaling in vascular smooth muscle cells from β-arrestin–dependent proliferation to G protein–dependent hypertrophy. These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II..
5. Nakaya Michio, , Tajima M, Hashimoto A, Motohiro Nishida, Hitoshi Kurose, GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance., Nature Communications, doi: 10.1038/ncomms2540, 4, 1532, 2013.04.
6. Motohiro Nishida, 北島直幸, Hitoshi Kurose, Recombinant mitochondrial transcription factor A protein inhibits nuclear factor of activated T cells signaling and attenuates pathological hypertrophy of cardiac myocytes., Mitochondrion, 12, 449-458, 2012.09.
7. Motohiro Nishida, 北島直幸, Hitoshi Kurose, Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration., Nature Chemical Biology, 8, 714-724, 2012.07, クスリはリスクである反面、毒も低用量で使えば薬になりうる。硫化水素は呼吸停止を誘発する猛毒ガスとして知られている。我々は、低用量の硫化水素が心筋梗塞後の慢性心不全を抑制することを初めて明らかにした。すなわち、硫化水素(H2S)はpH7.4の溶液中でほとんどが求核性の高いアニオン(HS-)として存在し、生体内で生じる親電子物質と反応し、これを消去することを新たに見出した。マウス心臓では、心筋梗塞後の心臓に8-nitro-cGMPをはじめとする親電子性の高い酸化物質が生成し、親電子物質が細胞内シグナルタンパク質の一つであるH-Ras(GTP結合タンパク質)に機能修飾を与え、心筋老化を誘導することがわかった。HS-はこれを直接抑制することで心不全を改善することを個体レベルで実証した。.
8. Kitajima N, Watanabe K, Morimoto S, Sato Y, Kiyonaka S, Hoshijima M, Ikeda Y, Nakaya M, Ide T, Mori Y, Kurose H and Nishida M., TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts., Biochemical Biophysical Research Communications, 409, 108-113, 2011.05.
9. Nishida M, Ogushi M, Suda R, Toyotaka M, Saiki S, Kitajima N, Nakaya M, Kim K-M, Ide T, Sato Y, Inoue K and Kurose H., Heterologous down-regulation of angiotensin type1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-kB., Proceedings of National Academy of Sciences USA, 108, 6662-6667, 2011.04, 遺伝子の構成成分である核酸(ヌクレオチド)は細胞外で重要なシグナル伝達物質として働くことが知られている。しかし、心臓における細胞外ヌクレオチドの役割についてはよくわかっていない。我々は、細胞外ヌクレオチドが細胞内で一酸化窒素の生成を誘導することで炎症性の転写因子(NF-kB)を抑制し、結果的に心血管病の重要仲介因子であるアンジオテンシンIIの作用する受容タンパク質(AT1受容体)の発現量を低下させることを見出した。細胞外ヌクレオチドは高血圧などの物理的圧負荷によって遊離されることから、細胞外ヌクレオチドがレニン・アンジオテンシン系の負のチューナーとして働く可能性が初めて示された。.
10. Nishida M, Ogushi M, Suda R, Toyotaka M, Saiki S, Kitajima N, Nakaya M, Kim K-M, Ide T, Sato Y, Inoue K and Kurose H, Heterologous down-regulation of angiotensin type1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-kB., Proc. Natl. Acad. Sci. USA., 10.1073/pnas.1017640108, 108, 6662-6667, 2011.04.
11. Kinoshita H, Kuwahara K, Nishida M, Jiang Z, Rong X, Kiyonaka S, Kuwabara Y, Kurose H, Inoue R, Mori Y, Li Y, Nakagawa Y, Usami S, Fujiwara M, Yamada Y, Minami T, Ueshima K and Nakao K., Inhibition of TRPC6 channel activity contributes to the anti-hypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart., Circulation Research, in press, 2010.06.
12. Nishida M, Watanabe K, Sato Y, Nakaya M, Kitajima K, Ide T, Inoue R and Kurose H., Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition., J. Biol. Chem., 285, 13244-13253, 2010.05, ctivation of Ca2+ signaling induced by receptor stimulation and mechanical stress plays a critical role in the development of cardiac hypertrophy. A canonical transient receptor potential protein subfamily member TRPC6, which is activated by diacylglycerol (DAG) and mechanical stretch, works as an upstream regulator of Ca2+ signaling pathway. Although activation of protein kinase G (PKG) inhibits TRPC6 channel activity and cardiac hypertrophy, respectively, it is unclear whether PKG suppresses cardiac hypertrophy through inhibition of TRPC6. Here, we show that inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppresses endothelin-1-, DAG analog- and mechanical stretch-induced hypertrophy through inhibition of Ca2+ influx in rat neonatal cardiomyocytes. Inhibition of PDE5 suppressed the increase in frequency of Ca2+ spikes induced by agonists or mechanical stretch. However, PDE5 inhibition did not suppress the hypertrophic responses induced by high KCl or the activation of protein kinase C, suggesting that PDE5 inhibition suppresses Ca2+ influx itself or molecule(s) upstream of Ca2+ influx. PKG activated by PDE5 inhibition phosphorylated TRPC6 proteins at Thr69 and prevented TRPC6-mediated Ca2+ influx. Substitution of Ala for Thr69 in TRPC6 abolished the anti-hypertrophic effects of PDE5 inhibition. In addition, chronic PDE5 inhibition by oral sildenafil treatment actually induced TRPC6 phosphorylation in mouse hearts. Knockdown of regulator of G protein signaling 2 (RGS2) and RGS4, both of which are activated by PKG to reduce Gαq-mediated signaling, did not affect the suppression of receptor-activated Ca2+ influx by PDE5 inhibition. These results suggest that phosphorylation and functional suppression of TRPC6 underlies prevention of pathological hypertrophy by PDE5 inhibition..
13. Nishida M, Suda R, Tanabe S, Onohara N, Nakaya M, Kanaho Y, Sumimoto H, Sato Y and Kurose H., Pertussis toxin upregulates angiotensin type1 receptors through TLR4-mediated Rac activation., J. Biol. Chem., 285, 15268-15277, 2010.05, Pertussis toxin (PTX) is recognized as a specific tool that uncouples receptors from Gi and Go through ADP-ribosylation. During the study analyzing the effects of PTX on AT1R function in cardiac fibroblasts, we found that PTX increases the number of angiotensin type 1 receptor (AT1R) and enhances AT1R-mediated response. Microarray analysis revealed that PTX increases the induction of interleukin (IL)-1β among cytokines. Inhibition of IL-1β suppressed the enhancement of AT1R-mediated response by PTX. PTX increased the expression of IL-1β and AT1R through NF-κB, and a small GTP-binding protein Rac mediated PTX-induced NF-κB activation through NADPH oxidase-dependent production of reactive oxygen species. PTX induced biphasic increases in Rac activity and the Rac activation in a late but not an early phase was suppressed by IL-1β siRNA, suggesting that IL-1β-induced Rac activation contributes to the amplification of Rac-dependent signaling induced by PTX. Furthermore, inhibition of Toll-like receptor 4 (TLR4) abolished PTX-induced Rac activation and enhancement of AT1R function. However, ADP-ribosylation of Gi/Go by PTX was not affected by inhibition of TLR4. Thus, PTX binds to two receptors: one is TLR4 that activates Rac, and another is the binding site that is required for ADP-ribosylation of Gi /Go..
14. Numaga T, Nishida M, Kiyonaka S, Kato K, Katano M, Mori E, Kurosaki T, Inoue R, Hikida M, Putney JW Jr, and Mori Y., Ca2+ influx and protein scaffolding via TRPC3 sustain PKCβ and ERK activation in B cells., Journal of Cell Science, 123, 927-938, 2010.03.
15. Kiyonaka S, Kato K, Nishida M, Mio K, Numaga T, Sawaguchi Y, Yoshida T, Wakamori M, Mori E, Numata T, Ishii M, Takemoto H, Ojida A, Watanabe K, Uemura A, Kurose H, Morii T, Kobayashi T, Sato Y, Sato C, Hamachi I and Mori Y., Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound., Proc Natl Acad Sci USA. , Vol. 106, No.13, 5400-5405, 2009.03.
16. Nishida M, Sato Y, Uemura A, Narita Y, Tozaki-Saitoh H, Nakaya M, Ide T, Suzuki K, Inoue K, Nagao T & Kurose H., P2Y6 receptor-Ga12/13 signalling in cardiomyocytes triggers pressure overload-induced cardiac fibrosis, The EMBO Journal, Vol27, No.23, 3104-3115, 2008.12.
17. Nishida M, Onohara N, Sato Y, Suda R, Ogushi M, Tanabe S, Inoue R, Mori Y & Kurose H., Galpha12/13-mediated upregulation of TRPC6 negatively regulates endothelin-1-induced cardiac myofibroblast formation and collagen synthesis through NFAT activation., The Journal of Biological Chemistry, 282, 23117-23128, 2007.08.
18. Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H, Sato Y, Mori Y, Nagao T & Kurose H., TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy., The EMBO Journal, 25, 5305-5316, 2006.11.
19. Nishida M, Tanabe S, Maruyama Y, Mangmool S, Urayama K, Nagamatsu Y, Takagahara S, Turner JH, Kozasa T, Kobayashi H, Sato Y, Kawanishi T, Inoue R, Nagao T, and Kurose H., Ga12/13-and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 MAPK by angiotensin receptor stimulation in rat neonatal cardiomyocytes., The Journal of Biological Chemistry, 10.1074/jbc.M409710200, 280, 18, 18434-18441, 280, 18434-18441, 2005.04.
20. Nishida M, Sugimoto K, Hara Y, Mori E, Morii T, Kurosaki T & Mori Y, Amplification of receptor signalling by Ca2+ entry-mediated translocation and activation of PLCg2 in B lymphocytes., The EMBO Journal, 22, 4677-4688, 2003.09.
21. Nishida M, Schey KL, Takagahara S, Kontani K, Katada T, Urano Y, Nagano T, Nagao T & Kurose H, Activation mechanism of Gi and Go by reactive oxygen species., The Journal of Biological Chemistry, 277, 9036-9042, 2002.03.
22. Nishida M, Takagahara S, Maruyama Y, Sugimoto Y, Nagao T & Kurose H, Gbg counteracts Gaq signaling upon a1-adrenergic receptor stimulation., Biochemical and Biophysical Research Communication, 291, 995-1000, 2002.02.
23. Nishida M, Maruyama Y, Tanaka R, Kontani K, Nagao T, & Kurose H, Gai and Gao are target proteins of reactive oxygen species., Nature, 408, 492-495, 2000.12.
24. Nishida M, Urushidani T, Sakamoto K & Nagao T, l-cis Diltiazem attenuates intracellular Ca2+ overload by metabolic inhibition in guinea pig myocytes., The European Journal of Pharmacology, 385, 225-230, 1999.12.
25. Nishida M, Nagao T & Kurose H, Activation of Rac1 increases c-Jun NH2-terminal kinase activity and DNA fragmentation in a calcium-dependent manner in rat myoblast cell line H9c2., Biochemical and Biophysical Research Communication, 262, 350-354, 1999.08.
26. Nishida M, Sakamoto K, Urushidani T & Nagao T, Treatment with l-cis diltiazem before reperfusion reduces infarct size in the ischemic rabbit heart in vivo., The Journal of Pharmaceutical Sciences, 80, 319-325, 1999.07.
1. 西田 基宏, Regulation of cardiac oxygen remodeling via electrophilic modification of Drp1, The 89th Annual Meeting of the Japanese Biochemical Society, 2017.09.
2. 西田 基宏, New strategies for drug development of heart failure, Medical Research Seminar in Malaysia Sabah University, 2017.01.
3. 西田 基宏, Myocardial early senescence mediated by mitochondria-cytoskeleton interaction, The 39th Annual Meeting of the Molecular Biology Society of Japan, 2016.12, Myocardial early senescence mediated by mitochondria-cytoskeleton interaction.
4. 西田 基宏, TRPC channels in cardiovascular stress resilience, International and Interdisciplinary Symposium 2016 “Towards a New Era of Cardiovascular Research, 2016.07.
5. 西田 基宏, Redox regulation of G proteins in cardiac remodeling, The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide, 2016.05.
Membership in Academic Society
  • Physiological Society of Japan
  • Society for Free Radical Research Japan
  • International Society for Heart Research
  • Hydrogen sulfide suppresses H-Ras-mediated cardiac senescence after myocardial infarction via electrophilic sulfhydration
  • Roles of Heterotrimeric GTP-binding Proteins in the Progression of Heart Failure
  • ATP decreases angiotensin type 1 receptor expression through S-nitrosylation of nuclear factor κB
Educational Activities
Pharmacology I
Practical Training of Research Technique
Presentation Practice I, II in Clinical Pharmaceutics
Advanced Research in Clinical Pharmaceutics