Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Motohiro Nishida Last modified date:2020.01.10

Professor / Department of Translational Pharmaceutical Sciences / Department of Pharmaceutical Health Care and Sciences / Faculty of Pharmaceutical Sciences

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. Numaga-Tomita T, Shimauchi T, Oda S, Tanaka T, Nishiyama K, Nishimura A, Birnbaumer L, Mori Y, Nishida M, TRPC6 regulates phenotypic switching of vascular smooth muscle cells through plasma membrane potential-dependent coupling with PTEN., FASEB Journal, 10.1096/fj.201802811R., 33, 9, 9785-9796, 2019.09.
3. Sudi SB, Tanaka T, Oda S, Nishiyama K, Nishimura A, Sunggip C, Mangmool S, Numaga-Tomita T, Nishida M, TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy., Scientific Reports, 10.1038/s41598-019-46252-2, 9, 1, 9785, 2019.07.
4. 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.
5. Takuro Numaga-Tomita, Sayaka Oda, Kazuhiro Nishiyama, Tomohiro Tanaka, Akiyuki Nishimura, Motohiro Nishida, TRPC channels in exercise-mimetic therapy, Pflugers Archiv European Journal of Physiology, 10.1007/s00424-018-2211-3, 471, 3, 507-517, 2019.03, Physical exercise yields beneficial effects on all types of muscle cells, which are essential for the maintenance of cardiovascular homeostasis and good blood circulation. Daily moderate exercise increases systemic antioxidative capacity, which can lead to the prevention of the onset and progression of oxidative stress-related diseases. Therefore, exercise is now widely accepted as one of the best therapeutic strategies for the treatment of ischemic (hypoxic) diseases. Canonical transient receptor potential (TRPC) proteins are non-selective cation channels activated by mechanical stress and/or stimulation of phospholipase C-coupled surface receptors. TRPC channels, especially diacylglycerol-activated TRPC channels (TRPC3 and TRPC6; TRPC3/6), play a key role in the development of cardiovascular remodeling. We have recently found that physical interaction between TRPC3 and NADPH oxidase (Nox) 2 under hypoxic stress promotes Nox2-dependent reactive oxygen species (ROS) production and mediates rodent cardiac plasticity, and inhibition of the TRPC3-Nox2 protein complex results in enhancement of myocardial compliance and flexibility similar to that observed in exercise-treated hearts. In this review, we describe current understanding of the roles of TRPC channels in striated muscle (patho)physiology and propose that targeting TRPC-based protein complexes could be a new strategy to imitate exercise therapy..
6. Hideshi Ihara, Yuki Kakihana, Akane Yamakage, Kenji Kai, Takahiro Shibata, Motohiro Nishida, Ken-Ichi Yamada, Koji Uchida, 2-Oxo-histidine-containing dipeptides are functional oxidation products, Journal of Biological Chemistry, 10.1074/jbc.RA118.006111, 294, 4, 1279-1289, 2019.01, Imidazole-containing dipeptides (IDPs), such as carnosine and anserine, are found exclusively in various animal tissues, especially in the skeletal muscles and nerves. IDPs have antioxidant activity because of their metal-chelating and free radical-scavenging properties. However, the underlying mechanisms that would fully explain IDP antioxidant effects remain obscure. Here, using HPLC- electrospray ionization-tandem MS analyses, we comprehensively investigated carnosine and its related small peptides in the soluble fractions of mouse tissue homogenates and ubiquitously detected 2-oxo-histidine-containing dipeptides (2-oxo-IDPs) in all examined tissues. We noted enhanced production of the 2-oxo-IDPs in the brain of a mouse model of sepsis-associated encephalopathy. Moreover, in SH-SY5Y human neuroblastoma cells stably expressing carnosine synthase, H
exposure resulted in the intracellular production of 2-oxo-carnosine, which was associated with significant inhibition of the H
cytotoxicity. Notably, 2-oxo-carnosine showed a better antioxidant activity than endogenous antioxidants such as GSH and ascorbate. Mechanistic studies indicated that carnosine monooxygenation is mediated through the formation of a histidyl-imidazole radical, followed by the addition of molecular oxygen. Our findings reveal that 2-oxo-IDPs are metal-catalyzed oxidation products present in vivo and provide a revised paradigm for understanding the antioxidant effects of the IDPs..
7. Tomohiro Tanaka, Akiyuki Nishimura, Kazuhiro Nishiyama, Takumi Goto, Takuro Numaga-Tomita, Motohiro Nishida, Mitochondrial dynamics in exercise physiology, Pflugers Archiv European Journal of Physiology, 10.1007/s00424-019-02258-3, 2019.01, A growing body of evidence suggests that exercise shows pleiotropic effects on the maintenance of systemic homeostasis through mitochondria. Dysregulation of mitochondrial dynamism is associated with metabolic inflexibility, resulting in many of the metabolic diseases and aging. Studies have suggested that exercise prevents and delays the progression of mitochondrial dysfunction by improving mitochondrial metabolism, biogenesis, and quality control. Exercise modulates functions of mitochondrial dynamics-regulating proteins through post-translational modification mechanisms. In this review, we discuss the putative mechanisms underlying maintenance of mitochondrial homeostasis by exercise, especially focusing on the post-translational modifications of several signaling proteins contributing to mitochondrial biogenesis, autophagy or mitophagy flux, and fission/fusion cycle. We also introduce novel small molecules that can potentially mimic exercise therapy through preserving mitochondrial dynamism. These recent advancements in the field of mitochondrial biology may lead to a greater understanding of exercise signaling..
8. Akiyuki Nishimura, Tsukasa Shimauchi, Tomohiro Tanaka, Kakeru Shimoda, Takashi Toyama, Naoyuki Kitajima, Tatsuya Ishikawa, Naoya Shindo, Takuro Numaga-Tomita, Satoshi Yasuda, Yoji Sato, Koichiro Kuwahara, Yoshito Kumagai, Takaaki Akaike, Tomomi Ide, Akio Ojida, Yasuo Mori, Motohiro Nishida, Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence, Science Signaling, 10.1126/scisignal.aat5185, 11, 556, 2018.11, Defective mitochondrial dynamics through aberrant interactions between mitochondria and actin cytoskeleton is increasingly recognized as a key determinant of cardiac fragility after myocardial infarction (MI). Dynamin-related protein 1 (Drp1), a mitochondrial fission-accelerating factor, is activated locally at the fission site through interactions with actin. Here, we report that the actin-binding protein filamin A acted as a guanine nucleotide exchange factor for Drp1 and mediated mitochondrial fission-associated myocardial senescence in mice after MI. In peri-infarct regions characterized by mitochondrial hyperfission and associated with myocardial senescence, filamin A colocalized with Drp1 around mitochondria. Hypoxic stress induced the interaction of filamin A with the GTPase domain of Drp1 and increased Drp1 activity in an actin-binding-dependent manner in rat cardiomyocytes. Expression of the A1545T filamin mutant, which potentiates actin aggregation, promoted mitochondrial hyperfission under normoxia. Furthermore, pharmacological perturbation of the Drp1-filamin A interaction by cilnidipine suppressed mitochondrial hyperfission-associated myocardial senescence and heart failure after MI. Together, these data demonstrate that Drp1 association with filamin and the actin cytoskeleton contributes to cardiac fragility after MI and suggests a potential repurposing of cilnidipine, as well as provides a starting point for innovative Drp1 inhibitor development..
9. Warisara Parichatikanond, Akiyuki Nishimura, Motohiro Nishida, Supachoke Mangmool, Prolonged stimulation of β2-adrenergic receptor with β2-agonists impairs insulin actions in H9c2 cells, Journal of Pharmacological Sciences, 10.1016/j.jphs.2018.09.007, 138, 3, 184-191, 2018.11, Insulin resistance is a condition in which there is a defect in insulin actions to induce glucose uptake into the cells. Overstimulation of β2-adrenergic receptors (β2ARs) is associated with the pathogenesis of insulin resistance in the heart. However, the mechanisms by which β2-agonists affect insulin resistance in the heart are incompletely understood. The β2-agonists are used for treatment of asthma due to bronchodilating effects. We also investigated the effects of β2-agonists in human bronchial smooth muscle (HBSM) cells. In this study, we demonstrate that chronic treatment with salbutamol, salmeterol, and formoterol inhibited insulin-induced glucose uptake and GLUT4 synthesis in H9c2 myoblast cells. Sustained β2AR stimulation also attenuated GLUT4 translocation to the plasma membrane, whereas short-term stimulation had no effect. In HBSM cells, prolonged treatment with β2-agonists had no effect on insulin-induced glucose uptake and did not alter insulin-induced expressions of GLUT1, GLUT4, and GLUT10. In addition, genetic polymorphisms at amino acid positions 16 and 27 of β2AR are linked to insulin resistance by significant suppression of GLUT4 translocation compared to wild-type. Thus, prolonged β2AR stimulation by β2-agonists impairs insulin actions through suppression of GLUT synthesis and translocation only in H9c2 cells..
10. Caroline Sunggip, Kakeru Shimoda, Sayaka Oda, Tomohiro Tanaka, Kazuhiro Nishiyama, Supachoke Mangmool, Akiyuki Nishimura, Takuro Numaga-Tomita, Motohiro Nishida, TRPC5-eNOS axis negatively regulates ATP-induced cardiomyocyte hypertrophy, Frontiers in Pharmacology, 10.3389/fphar.2018.00523, 9, MAY, 2018.05, Cardiac hypertrophy, induced by neurohumoral factors, including angiotensin II and endothelin-1, is a major predisposing factor for heart failure. These ligands can induce hypertrophic growth of neonatal rat cardiomyocytes (NRCMs) mainly through Ca2+-dependent calcineurin/nuclear factor of activated T cell (NFAT) signaling pathways activated by diacylglycerol-activated transient receptor potential canonical 3 and 6 (TRPC3/6) heteromultimer channels. Although extracellular nucleotide, adenosine 5'-triphosphate (ATP), is also known as most potent Ca2+-mobilizing ligand that acts on purinergic receptors, ATP never induces cardiomyocyte hypertrophy. Here we show that ATP-induced production of nitric oxide (NO) negatively regulates hypertrophic signaling mediated by TRPC3/6 channels in NRCMs. Pharmacological inhibition of NO synthase (NOS) potentiated ATP-induced increases in NFAT activity, protein synthesis, and transcriptional activity of brain natriuretic peptide. ATP significantly increased NO production and protein kinase G (PKG) activity compared to angiotensin II and endothelin-1. We found that ATP-induced Ca2+ signaling requires inositol 1,4,5-trisphosphate (IP3) receptor activation. Interestingly, inhibition of TRPC5, but not TRPC6 attenuated ATP-induced activation of Ca2+/NFAT-dependent signaling. As inhibition of TRPC5 attenuates ATP-stimulated NOS activation, these results suggest that NO-cGMP-PKG axis activated by IP3-mediated TRPC5 channels underlies negative regulation of TRPC3/6-dependent hypertrophic signaling induced by ATP stimulation..
11. Yohei Yamaguchi, Gentaro Iribe, Toshiyuki Kaneko, Ken Takahashi, Takuro Numaga-Tomita, Motohiro Nishida, Lutz Birnbaumer, Keiji Naruse, TRPC3 participates in angiotensin II type 1 receptor-dependent stress-induced slow increase in intracellular Ca2+ concentration in mouse cardiomyocytes, Journal of Physiological Sciences, 10.1007/s12576-016-0519-3, 68, 2, 153-164, 2018.03, When a cardiac muscle is held in a stretched position, its [Ca2+] transient increases slowly over several minutes in a process known as stress-induced slow increase in intracellular Ca2+ concentration ([Ca2+]i) (SSC). Transient receptor potential canonical (TRPC) 3 forms a non-selective cation channel regulated by the angiotensin II type 1 receptor (AT1R). In this study, we investigated the role of TRPC3 in the SSC. Isolated mouse ventricular myocytes were electrically stimulated and subjected to sustained stretch. An AT1R blocker, a phospholipase C inhibitor, and a TRPC3 inhibitor suppressed the SSC. These inhibitors also abolished the observed SSC-like slow increase in [Ca2+]i induced by angiotensin II, instead of stretch. Furthermore, the SSC was not observed in TRPC3 knockout mice. Simulation and immunohistochemical studies suggest that sarcolemmal TRPC3 is responsible for the SSC. These results indicate that sarcolemmal TRPC3, regulated by AT1R, causes the SSC..
12. Kumiko Masuda, Hiroyasu Tsutsuki, Shingo Kasamatsu, Tomoaki Ida, Tsuyoshi Takata, Kikuya Sugiura, Motohiro Nishida, Yasuo Watanabe, Tomohiro Sawa, Takaaki Akaike, Hideshi Ihara, Involvement of nitric oxide/reactive oxygen species signaling via 8-nitro-cGMP formation in 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells and rat cerebellar granule neurons, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.12.088, 495, 3, 2165-2170, 2018.01, To investigate the role of nitric oxide (NO)/reactive oxygen species (ROS) redox signaling in Parkinson's disease-like neurotoxicity, we used 1-methyl-4-phenylpyridinium (MPP+) treatment (a model of Parkinson's disease). We show that MPP+-induced neurotoxicity was dependent on ROS from neuronal NO synthase (nNOS) in nNOS-expressing PC12 cells (NPC12 cells) and rat cerebellar granule neurons (CGNs). Following MPP+ treatment, we found production of 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP), a second messenger in the NO/ROS redox signaling pathway, in NPC12 cells and rat CGNs, that subsequently induced S-guanylation and activation of H-Ras. Additionally, following MPP+ treatment, extracellular signal-related kinase (ERK) phosphorylation was enhanced. Treatment with a mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor attenuated MPP+-induced ERK phosphorylation and neurotoxicity. In conclusion, we demonstrate for the first time that NO/ROS redox signaling via 8-nitro-cGMP is involved in MPP+-induced neurotoxicity and that 8-nitro-cGMP activates H-Ras/ERK signaling. Our results indicate a novel mechanism underlying MPP+-induced neurotoxicity, and therefore contribute novel insights to the mechanisms underlying Parkinson's disease..
13. Licht Miyamoto, Motohiro Nishida, Lifestyle inspires future pharmacotherapy and drug discovery, Yakugaku Zasshi, 10.1248/yakushi.18-00091-F, 138, 10, 1255-1256, 2018.01.
14. Sayaka Oda, Takuro Numaga-Tomita, Motohiro Nishida, New strategies for exercise-mimetic medication, Yakugaku Zasshi, 10.1248/yakushi.18-00091-1, 138, 10, 1257-1262, 2018.01, Moderate exercise has been reported to combat several diseases, including cardiovascular diseases and depressants. However, many patients do not have ability to undergo exercise therapy due to aging and severity of the symptoms. Therefore development of new drugs that can imitate exercise therapy is desired and actually studied worldwide. The heart is one of the physical load-responsive target organs such as skeletal muscles and vascular smooth muscles. The heart can adapt from environmental stress by changing its structure and morphology (i.e., remodeling). Physiological remodeling, caused by exercise or pregnancy, can be defined by compensative and reversible changes to the heart, whereas pathological remodeling can be defined by irreversible changes of the heart, through aberrant calcium ion (Ca

) signaling as well as production of reactive oxygen species (ROS). However, crosstalk between Ca

and ROS remains obscure. In this review we will introduce our recent findings on the functional crosstalk between transient receptor potential canonical (TRPC) 3 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) 2 as a novel molecular target to mimic exercise therapy..
15. Tomohiro Sawa, Katsuhiko Ono, Hiroyasu Tsutsuki, Tianli Zhang, Tomoaki Ida, Motohiro Nishida, Takaaki Akaike, Reactive Cysteine Persulphides
Occurrence, Biosynthesis, Antioxidant Activity, Methodologies, and Bacterial Persulphide Signalling, Nitric Oxide and Other Small Signalling Molecules, 10.1016/bs.ampbs.2018.01.002, 1-28, 2018.01, Cysteine hydropersulphide (CysSSH) is a cysteine derivative having one additional sulphur atom bound to a cysteinyl thiol group. Recent advances in the development of analytical methods for detection and quantification of persulphides and polysulphides have revealed the biological presence, in both prokaryotes and eukaryotes, of hydropersulphides in diverse forms such as CysSSH, homocysteine hydropersulphide, glutathione hydropersulphide, bacillithiol hydropersulphide, coenzyme A hydropersulphide, and protein hydropersulphides. Owing to the chemical reactivity of the persulphide moiety, biological systems utilize persulphides as important intermediates in the synthesis of various sulphur-containing biomolecules. Accumulating evidence has revealed another important feature of persulphides: their potent reducing activity, which implies that they are implicated in the regulation of redox signalling and antioxidant functions. In this chapter, we discuss the biological occurrence and possible biosynthetic mechanisms of CysSSH and related persulphides, and we include descriptions of recent advances in the analytical methods that have been used to detect and quantitate persulphide species. We also discuss the antioxidant activity of persulphide species that contributes to protecting cells from reactive oxygen species-associated damage, and we examine the signalling roles of CysSSH in bacteria..
16. Takaaki Akaike, Tomoaki Ida, Fan Yan Wei, Motohiro Nishida, Yoshito Kumagai, Md Morshedul Alam, Hideshi Ihara, Tomohiro Sawa, Tetsuro Matsunaga, Shingo Kasamatsu, Akiyuki Nishimura, Masanobu Morita, Kazuhito Tomizawa, Akira Nishimura, Satoshi Watanabe, Kenji Inaba, Hiroshi Shima, Nobuhiro Tanuma, Minkyung Jung, Shigemoto Fujii, Yasuo Watanabe, Masaki Ohmuraya, Péter Nagy, Martin Feelisch, Jon M. Fukuto, Hozumi Motohashi, Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics, Nature Communications, 10.1038/s41467-017-01311-y, 8, 1, 2017.12, Cysteine hydropersulfide (CysSSH) occurs in abundant quantities in various organisms, yet little is known about its biosynthesis and physiological functions. Extensive persulfide formation is apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is believed to result from post-translational processes involving hydrogen sulfide-related chemistry. Here we demonstrate effective CysSSH synthesis from the substrate l-cysteine, a reaction catalyzed by prokaryotic and mammalian cysteinyl-tRNA synthetases (CARSs). Targeted disruption of the genes encoding mitochondrial CARSs in mice and human cells shows that CARSs have a crucial role in endogenous CysSSH production and suggests that these enzymes serve as the principal cysteine persulfide synthases in vivo. CARSs also catalyze co-translational cysteine polysulfidation and are involved in the regulation of mitochondrial biogenesis and bioenergetics. Investigating CARS-dependent persulfide production may thus clarify aberrant redox signaling in physiological and pathophysiological conditions, and suggest therapeutic targets based on oxidative stress and mitochondrial dysfunction..
17. Akiyuki Nishimura, Caroline Sunggip, Sayaka Oda, Takuro Numaga-Tomita, Tsuda Makoto, Motohiro Nishida, Purinergic P2Y receptors
Molecular diversity and implications for treatment of cardiovascular diseases, Pharmacology and Therapeutics, 10.1016/j.pharmthera.2017.06.010, 180, 113-128, 2017.12, Purinergic signaling, mediated mainly by G protein-coupled P2Y receptors (P2YRs), is now attracting attention as a new therapeutic target for preventing or treating cardiovascular diseases. Observations using mice with genetically modified P2YRs and/or treated with a pharmacological P2YR inhibitor have helped us understand the physiological and pathological significance of P2YRs in the cardiovascular system. P2YR-mediated biological functions are predominantly activated by mononucleotides released from non-adrenergic, non-cholinergic nerve endings or non-secretory tissues in response to physical stress or cell injury, though recent studies have suggested the occurrence of ligand-independent P2YR function through receptor-receptor interactions (oligomerization) in several biological processes. In this review, we introduce the functions of P2YRs and possible dimerization with G protein-coupled receptors (GPCRs) in the cardiovascular system. We focus especially on the crosstalk between uridine nucleotide-responsive P2Y6R and angiotensin (Ang) II type1 receptor (AT1R) signaling, and introduce our recent finding that the P2Y6R antagonist MRS2578 interrupts heterodimerization between P2Y6R and AT1R, thereby reducing the risk of AT1R-stimulated hypertension in mice. These results strongly suggest that targeting P2Y6R oligomerization could be an effective new strategy to reduce the risk of cardiovascular diseases..
18. 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..
19. Caroline Sunggip, Akiyuki Nishimura, Kakeru Shimoda, Takuro Numaga-Tomita, Tsuda Makoto, Motohiro Nishida, Purinergic P2Y6 receptors
A new therapeutic target of age-dependent hypertension, Pharmacological Research, 10.1016/j.phrs.2017.03.013, 120, 51-59, 2017.06, Aging has a remarkable effect on cardiovascular homeostasis and it is known as the major non-modifiable risk factor in the development of hypertension. Medications targeting sympathetic nerve system and/or renin-angiotensin-aldosterone system are widely accepted as a powerful therapeutic strategy to improve hypertension, although the control rates remain unsatisfactory especially in the elder patients with hypertension. Purinergic receptors, activated by adenine, uridine nucleotides and nucleotide sugars, play pivotal roles in many biological processes, including platelet aggregation, neurotransmission and hormone release, and regulation of cardiovascular contractility. Since clopidogrel, a selective inhibitor of G protein-coupled purinergic P2Y12 receptor (P2Y12R), achieved clinical success as an anti-platelet drug, P2YRs has been attracted more attention as new therapeutic targets of cardiovascular diseases. We have revealed that UDP-responsive P2Y6R promoted angiotensin type 1 receptor (AT1R)-stimulated vascular remodeling in mice, in an age-dependent manner. Moreover, the age-related formation of heterodimer between AT1R and P2Y6R was disrupted by MRS2578, a P2Y6R-selective inhibitor. These findings suggest that P2Y6R is a therapeutic target to prevent age-related hypertension..
20. Sarawuth Phosri, Ajaree Arieyawong, Kwanchai Bunrukchai, Warisara Parichatikanond, Akiyuki Nishimura, Motohiro Nishida, Supachoke Mangmool, Stimulation of adenosine A2B receptor inhibits endothelin-1-induced cardiac Fibroblast proliferation and α-smooth muscle actin synthesis through the cAMP/Epac/PI3K/Akt-signaling pathway, Frontiers in Pharmacology, 10.3389/fphar.2017.00428, 8, JUN, 2017.06, Background and Purpose: Cardiac fibrosis is characterized by an increase in fibroblast proliferation, overproduction of extracellular matrix proteins, and the formation of myofibroblast that express α-smooth muscle actin (α-SMA). Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac fibrosis. Overstimulation of endothelin receptors induced cell proliferation, collagen synthesis, and α-SMA expression in cardiac fibroblasts. Although adenosine was shown to have cardioprotective effects, the molecular mechanisms by which adenosine A2 receptor inhibit ET-1-induced fibroblast proliferation and α-SMA expression in cardiac fibroblasts are not clearly identified. Experimental Approach: This study aimed at evaluating the mechanisms of cardioprotective effects of adenosine receptor agonist in rat cardiac fibroblast by measurement of cell proliferation, and mRNA and protein levels of α-SMA. Key results: Stimulation of adenosine subtype 2B (A2B) receptor resulted in the inhibition of ET-1-induced fibroblast proliferation, and a reduction of ET-1-induced α-SMA expression that is dependent on cAMP/Epac/PI3K/Akt signaling pathways in cardiac fibroblasts. The data in this study confirm a critical role for Epac signaling on A2B receptor-mediated inhibition of ET-1-induced cardiac fibrosis via PI3K and Akt activation. Conclusion and Implications: This is the first work reporting a novel signaling pathway for the inhibition of ET-1-induced cardiac fibrosis mediated through the A2B receptor. Thus, A2B receptor agonists represent a promising perspective as therapeutic targets for the prevention of cardiac fibrosis..
21. Hideshi Ihara, Shingo Kasamatsu, Atsushi Kitamura, Akira Nishimura, Hiroyasu Tsutsuki, Tomoaki Ida, Kento Ishizaki, Takashi Toyama, Eiko Yoshida, Hisyam Abdul Hamid, Minkyung Jung, Tetsuro Matsunaga, Shigemoto Fujii, Tomohiro Sawa, Motohiro Nishida, Yoshito Kumagai, Takaaki Akaike, Exposure to electrophiles impairs reactive persulfide-dependent redox signaling in neuronal cells, Chemical Research in Toxicology, 10.1021/acs.chemrestox.7b00120, 30, 9, 1673-1684, 2017.01, Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitrocGMP), accompanied by depletion of reactive persulfide species and 8-SHcGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles..
22. Yasuaki Nakagawa, Toshio Nishikimi, Koichiro Kuwahara, Aoi Fujishima, Shogo Oka, Takayoshi Tsutamoto, Hideyuki Kinoshita, Kazuhiro Nakao, Kosai Cho, Hideaki Inazumi, Hiroyuki Okamoto, Motohiro Nishida, Takao Kato, Hiroyuki Fukushima, Jun K. Yamashita, Wino J. Wijnen, Esther E. Creemers, Kenji Kangawa, Naoto Minamino, Kazuwa Nakao, Takeshi Kimura, MiR30-GALNT1/2 axis-mediated glycosylation contributes to the increased secretion of inactive human prohormone for brain natriuretic peptide (proBNP) from failing hearts, Journal of the American Heart Association, 10.1161/JAHA.116.003601, 6, 2, 2017.01, Background-Recent studies have shown that plasma levels of the biologically inactive prohormone for brain natriuretic peptide (proBNP) are increased in patients with heart failure. This can contribute to a reduction in the effectiveness of circulating BNP and exacerbate heart failure progression. The precise mechanisms governing the increase in proBNP remain unclear, however. Methods and Results-We used our recently developed, highly sensitive human proBNP assay system to investigate the mechanisms underlying the increase in plasma proBNP levels. We divided 53 consecutive patients hospitalized with heart failure into 2 groups based on their aortic plasma levels of immunoreactive BNP. Patients with higher levels exhibited more severe heart failure, a higher proportion of proBNP among the immunoreactive BNP forms secreted from failing hearts, and a weaker effect of BNP as estimated from the ratio of plasma cyclic guanosine monophosphate levels to log-transformed plasma BNP levels. Glycosylation at threonines 48 and 71 of human proBNP contributed to the increased secretion of proBNP by attenuating its processing, and GalNAc-transferase (GALNT) 1 and 2 mediated the glycosylation-regulated increase in cardiac human proBNP secretion. Cardiac GALNT1 and 2 expression was suppressed by microRNA (miR)-30, which is abundantly expressed in the myocardium of healthy hearts, but is suppressed in failing hearts. Conclusions-We have elucidated a novel miR-30-GALNT1/2 axis whose dysregulation increases the proportion of inactive proBNP secreted by the heart and impairs the compensatory actions of BNP during the progression of heart failure..
23. Akiyuki Nishimura, Motohiro Nishida, Purinergic signaling in cardiovascular system, Folia Pharmacologica Japonica, 10.1254/fpj.149.84, 149, 2, 84-90, 2017.01.
24. Tsukasa Shimauchi, Akiyuki Nishimura, Tatsuya Ishikawa, Motohiro Nishida, Eco-pharma of approved drug focused on mitochondria fission, Folia Pharmacologica Japonica, 10.1254/fpj.149.269, 149, 6, 269-273, 2017.
25. Takuro Numaga-Tomita, Naoyuki Kitajima, Takuya Kuroda, Akiyuki Nishimura, Kei Miyano, Satoshi Yasuda, Koichiro Kuwahara, Yoji Sato, Tomomi Ide, Lutz Birnbaumer, Hideki Sumimoto, Yasuo Mori, Motohiro Nishida, TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis, Scientific Reports, 10.1038/srep39383, 6, 2016.12, Structural cardiac remodeling, accompanying cytoskeletal reorganization of cardiac cells, is a major clinical outcome of diastolic heart failure. A highly local Ca 2+ influx across the plasma membrane has been suggested to code signals to induce Rho GTPase-mediated fibrosis, but it is obscure how the heart specifically decodes the local Ca 2+ influx as a cytoskeletal reorganizing signal under the conditions of the rhythmic Ca 2+ handling required for pump function. We found that an inhibition of transient receptor potential canonical 3 (TRPC3) channel activity exhibited resistance to Rho-mediated maladaptive fibrosis in pressure-overloaded mouse hearts. Proteomic analysis revealed that microtubule-Associated Rho guanine nucleotide exchange factor, GEF-H1, participates in TRPC3-mediated RhoA activation induced by mechanical stress in cardiomyocytes and transforming growth factor (TGF) β stimulation in cardiac fibroblasts. We previously revealed that TRPC3 functionally interacts with microtubule-Associated NADPH oxidase (Nox) 2, and inhibition of Nox2 attenuated mechanical stretch-induced GEF-H1 activation in cardiomyocytes. Finally, pharmacological TRPC3 inhibition significantly suppressed fibrotic responses in human cardiomyocytes and cardiac fibroblasts. These results strongly suggest that microtubule-localized TRPC3-GEF-H1 axis mediates fibrotic responses commonly in cardiac myocytes and fibroblasts induced by physico-chemical stimulation..
26. Naoyuki Kitajima, Takuro Numaga-Tomita, Masahiko Watanabe, Takuya Kuroda, Akiyuki Nishimura, Kei Miyano, Satoshi Yasuda, Koichiro Kuwahara, Yoji Sato, Tomomi Ide, Lutz Birnbaumer, Hideki Sumimoto, Yasuo Mori, Motohiro Nishida, TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling, Scientific Reports, 10.1038/srep37001, 6, 2016.11, Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the transition from adaptation to maladaptation remains obscure, however. We demonstrate that transient receptor potential canonical 3 (TRPC3), a Ca 2+-permeable channel, acts as a positive regulator of ROS (PRROS) in cardiomyocytes, and specifically regulates pressure overload-induced maladaptive cardiac remodeling in mice. TRPC3 physically interacts with Nox2 at specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca 2+-dependent Nox2 activation through TRPC3-mediated background Ca 2+ entry. Nox2 also stabilizes TRPC3 proteins to enhance TRPC3 channel activity. Expression of TRPC3 C-terminal polypeptide abolished TRPC3-regulated ROS production by disrupting TRPC3-Nox2 interaction, without affecting TRPC3-mediated Ca 2+ influx. The novel TRPC3 function as a PRROS provides a mechanistic explanation for how diastolic Ca 2+ influx specifically encodes signals to induce ROS-mediated maladaptive remodeling and offers new therapeutic possibilities..
27. Takamitsu Unoki, Yumi Abiko, Takashi Toyama, Takashi Uehara, Koji Tsuboi, Motohiro Nishida, Toshiyuki Kaji, Yoshito Kumagai, Methylmercury, an environmental electrophile capable of activation and disruption of the Akt/CREB/Bcl-2 signal transduction pathway in SH-SY5Y cells, Scientific Reports, 10.1038/srep28944, 6, 2016.06, Methylmercury (MeHg) modifies cellular proteins via their thiol groups in a process referred to as "S-mercuration", potentially resulting in modulation of the cellular signal transduction pathway. We examined whether low-dose MeHg could affect Akt signaling involved in cell survival. Exposure of human neuroblastoma SH-SY5Y cells of up to 2 μM MeHg phosphorylated Akt and its downstream signal molecule CREB, presumably due to inactivation of PTEN through S-mercuration. As a result, the anti-apoptotic protein Bcl-2 was up-regulated by MeHg. The activation of Akt/CREB/Bcl-2 signaling mediated by MeHg was, at least in part, linked to cellular defence because either pretreatment with wortmannin to block PI3K/Akt signaling or knockdown of Bcl-2 enhanced MeHg-mediated cytotoxicity. In contrast, increasing concentrations of MeHg disrupted Akt/CREB/Bcl-2 signaling. This phenomenon was attributed to S-mercuration of CREB through Cys286 rather than Akt. These results suggest that although MeHg is an apoptosis-inducing toxicant, this environmental electrophile is able to activate the cell survival signal transduction pathway at lower concentrations prior to apoptotic cell death..
28. Shigemoto Fujii, Tomohiro Sawa, Motohiro Nishida, Hideshi Ihara, Tomoaki Ida, Hozumi Motohashi, Takaaki Akaike, Redox signaling regulated by an electrophilic cyclic nucleotide and reactive cysteine persulfides, Archives of Biochemistry and Biophysics, 10.1016/, 595, 140-146, 2016.04, Reactive oxygen (oxidant) and free radical species are known to cause nonspecific damage of various biological molecules. The oxidant toxicology is developing an emerging concept of the physiological functions of reactive oxygen species in cell signaling regulation. Redox signaling is precisely modulated by endogenous electrophilic substances that are generated from reactive oxygen species during cellular oxidative stress responses. Among diverse electrophilic molecular species that are endogenously generated, 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP) is a unique second messenger whose formation, signaling, and metabolism in cells was recently clarified. Most important, our current studies revealed that reactive cysteine persulfides that are formed abundantly in cells are critically involved in the metabolism of 8-nitro-cGMP. Modern redox biology involves frontiers of cell research and stem cell research; medical and clinical investigations of infections, cancer, metabolic syndrome, aging, and neurodegenerative diseases; and other fields. 8-Nitro-cGMP-mediated signaling and metabolism in cells may therefore be potential targets for drug development, which may lead to discovery of new therapeutic agents for many diseases..
29. 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..
30. 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.
31. 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.
32. 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。.
33. Nishioka K, Nishida M, Ariyoshi M, Saiki S, Jian Z, Hirano M, Nakaya M, Sato Y, Kita S, Iwamoto T, Hirano K, Inoue R and Kurose H, Protein kinase A-mediated phosphorylation of TRPC6 channels underlies suppression of angiotensin II-induced vasoconstriction., Arterioscler. Thromb. Vasc. Biol., 10.1161/ATVBAHA.110.221010, 31, 2278-2286, 2011.08.
34. 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.
35. 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., Arterioscler. Thromb. Vasc. Biol., 10.1016/j.bbrc.2011.04.124, 409, 108-113, 2011.05.
36. 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。.
37. Tomonari M, To H, Nishida M, Mishima T, Sasaki H, and Kurose H., Mechanism of the Cardioprotective Effects of Docetaxel Pre-administration Against Adriamycin-Induced Cardiotoxicity., Journal of Pharmacological Sciences, 115, 336-345, 2011.04.
38. Sugihara M, Morita H, Matsuda M, Umebayashi H, Kajioka S, Ito S, Nishida M, Inoue R, Futatsuki T, Yamazaki J, Mori Y, Inoue R, Ito Y, Abe K and Hirata M., Dual signaling pathways of arterial constriction by extracellular urine 5’-triphosphate in the rat., Journal of Pharmacological Sciences, 115, 293-308, 2011.04.
39. 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.
40. 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.
41. 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..
42. 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..
43. 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.
44. Yano T, Itoh Y, Kawamura E, Maeda A, Egashira N, Nishida M, Kurose H, Oishi R. , Amphotericin B-Induced Renal Tubular Cell Injury is Mediated by Na+ Influx through Ion-Permeable Pores and Subsequent Activation of MAP Kinases and Elevation of Intracellular Ca2+., Antimicrob Agents Chemother., Vol. 53, No.4, 1420-1426, 2009.04.
45. 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.
46. 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.
47. Shibata T, Nakahara H, Kita N, Matsubara Y, Han C, Morimitsu Y, Iwamoto N, Kumagai Y, Nishida M, Kurose H, Aoki N, Ojika M, Uchida K., A food-derived synergist of NGF signaling: Identification of protein tyrosine phosphatase 1B as a key regulator of NGF receptor-initiated signal transduction., J Neurochem., Vol. 107, 1248-1260, 2008.08.
48. Kusano Y, Horie S, Shibata T, Satsu H, Shimizu M, Hitomi E, Nishida M, Kurose H, Itoh K, Kobayashi A, Yamamoto M, Uchida K., Keap1 regulates the constitutive expression of GST A1 during differentiation of Caco-2 cells., Biochemistry, Vol. 47, 6169-7760, 2008.04.
49. 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.
50. 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.
51. Mangmool S, Haga T, Kobayashi H, Kim K-M, Nakata H, Nishida M & Kurose H., Clathrin regulates the activation of G protein-coupled receptor kinase 2 (GRK2) in cells but not in vitro., The Journal of Biological Chemistry, 281(42), 31940-31949, 2006.10.
52. Nagamatsu Y, Nishida M, Onohara N, Fukutomi M, Maruyama Y, Kobayashi H, Sato Y & Kurose H, Heterotrimeric G protein Ga13-induced expression of cytokine mRNAs through two distinct pathways in cardiac fibroblasts, The Journal of Pharmacological Sciences, 101, 144-150, 2006.06.
53. Yamazaki K, Shigetomi E, Ikeda R, Nishida M, Kiyonaka S, Mori Y & Kato F, Blocker-resistant presynaptic voltage-dependent Ca2+ channels underlying glutamate release from the visceral primary afferents in the nucleus tractus solitarii of the mice., Brain Research, 1104, 103-113, 2006.06.
54. Fukutomi M, Nishida M, Maruyama Y, Kobayashi H & Kurose H, Caveolae-independent activation of protein kinase A in rat neonatal myocytes, The Journal of Pharmacological Sciences, 10.1254/jphs.FP0050244, 98, 2, 168-174, 98, 168-174, 2005.09.
55. Fujii T, Onohara N, Maruyama Y, Tanabe S, Kobayashi H, Fukutomi M, Nagamatsu Y, Nishihara N, Inoue R, Sumimoto H, Shibasaki F, Nagao T, Nishida M & Kurose H., Ga12/13-mediated production of reactive oxygen species is critical for angiotensin receptor-induced NFAT activation in cardiac fibroblasts., The Journal of Biological Chemistry, 10.1074/jcb.M409397200, 280, 24, 23041-23047, 280, 23041-23047, 2005.06.
56. Okamura Y, Nishino A, Murata Y, Nakajo K, Iwasaki H, Ohtsuka Y, Tanaka-Kunishima M, Takahashi N, Hara Y, Yoshida T, Nishida M, Okado H, Watari H, Meinertzhagen IA, Satoh N, Takahashi K, Satou Y, Okada Y & Mori Y., Comprehensive analysis of the ascidian genome reveals novel insights into the molecular evolution of ion channel genes., Physiological Genomics, 22, 269-282, 2005.05.
57. 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.
58. Kobayashi H, Narita Y, Nishida M & Kurose H, β-Arrestin2 enhances β2-adrenergic receptor-mediated nuclear translocation of ERK., Cell Signaling, 10.1016/j.cellsig.2004.12.014, 17, 10, 1248-1253, 17, 1248-1253, 2005.02.
59. Suzuki T, Delgado-Escueta AV, Aguan K, Shi J, Alonso ME, Hara Y, Nishida M, Numata T, Takeuchi T, Morita R, Medina MT, Bai D, Ganesh S, Sugimoto Y, Inazawa J, Bailey JN, Ochoa A, Jara-Prado A, Rasmussen A, Ramos-Peek J, Cordova S, Rubio-Donnadieu F, Inoue, A gene mutated in juvenile myoclonic epilepsy encodes a protein regulating Cav2.3 channel., Nature Genetics, 36, 842-849, 2004.07.
60. Sugimoto K, Nishida M, Otsuka M, Ohkubo K, Mori Y & Morii T, Novel real time sensors to quantitatively assess in vivo inositol 1,4,5-trisphosphate production in intact cells., Chemistry and Biology, 11, 475-485, 2004.04.
61. 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.
62. Arai K, Maruyama Y, Nishida M, Tanabe S, Kozasa T, Mori Y, Nagao T & Kurose H, Endothelin-1-induced MAPK activation and cardiomyocyte hypertrophy are mediated by Ga12 and Ga13 as well as Gaq and Gbg subunits., Molecular Pharmacology, 63(3), 478-488, 2003.07.
63. Shimizu S, Shiota K, Yamamoto S, Miyasaka Y, Ishii M, Watabe T, Nishida M, Mori Y, Yamamoto T & Kiuchi Y, Hydrogen peroxide stimulates tetrahydrobiopterin synthesis through the induction of GTP-cyclohydrolase I and increases nitric oxide synthase activity in vascular endothelial cells., Free Radical Biology and Medicine, 34(10), 1343-1352, 2003.07.
64. Kitano J, Nishida M, Itsukaichi Y, Minami I, Ogawa M, Hirano T, Mori Y & Nakanishi S, Direct interaction and functional coupling between metabotropic glutamate receptor subtype 1 and voltage-sensitive Cav2.1 Ca2+ channel., The Journal of Biological Chemistry, 278, 25101-25108, 2003.06.
65. Maruyama Y, Nishida M, Sugimoto Y, Tanabe S, Turner JH, Kozasa T, Wada T, Nagao T & Kurose H, Ga12/13 mediate a1-adrenergic receptor-induced caradiac hypertrophy., Circulation Research, 10.1161/01.RES.0000043282.39776.7C, 91, 10, 961-969, 91, 961-969, 2002.11.
66. Mori Y, Wakamori M, Miyakawa T, Hermosura M, Hara Y, Nishida M, Hirose K, Mizushima A, Okada T, Kurosaki M, Mori E, Gotoh K, Fleig A, Penner R, Iino M & Kurosaki T, TRP1 regulates capacitative Ca2+ entry and Ca2+ release from endoplasmic reticulum in B lymphocytes., Journal of Experimental Medicine, 195, 673-681, 2002.03.
67. 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.
68. 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.
69. Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, Yoshida T, Yamada H, Shimizu S, Mori E, Kudoh J, Shimizu N, Kurose H, Okada Y, Imoto K & Mori Y, LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death., Molecular Cell, 9, 163-173, 2002.01.
70. 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.
71. 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.
72. 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.
73. 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.