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Akiyuki Nishimura Last modified date:2019.06.19

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


Graduate School
Undergraduate School


E-Mail
Phone
092-642-6556
Academic Degree
Ph.D (Bioscience)
Country of degree conferring institution (Overseas)
No
Field of Specialization
Biochemistry, Cell biology
Total Priod of education and research career in the foreign country
03years10months
Outline Activities
Research:
Study on signal transductions regulating environmental stress responses in cardiovascular systems.
Study on myocardial mitochondria regulating environmental stress responses.
Research
Research Interests
  • Environmental stress responses of cardiovascular system

    keyword : Cardiovascular, mitochondrial quality control, myocardial senescence, environmental stress response
    2018.09.
Academic Activities
Reports
1. Nishimura A., Sunggip C., Oda S., Numaga-Tomita T., Tsuda M. and Nishida M., Purinergic P2Y receptors: Molecular diversity and implications for treatment of cardiovascular diseases, Pharmacol. Ther., 2017.12.
2. Nishida M., Nishimura A., Matsunaga T., Motohashi H., Kasamatsu S. and Akaike T., Redox regulation of electrophilic signaling by reactive persulfides in cardiac cells, Free Rad. Biol. Med., 2017.08.
3. Sunggip C., Nishimura A., Shimoda K., Numaga-Tomita T., Tsuda M. and Nishida M., Purinergic P2Y6 receptors: A new therapeutic target of age-dependent hypertension, Pharmacol. Res., 2017.06.
Papers
1. 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..
2. 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..
3. Akiyuki Nishimura, Caroline Sunggip, Hidetoshi Saitoh, Tsukasa Shimauchi, Takuro Numaga-Tomita, Katsuya Hirano, Tomomi Ide, Jean Marie Boeynaems, Hitoshi Kurose, Tsuda Makoto, Bernard Robaye, Kazuhide Inoue, Motohiro Nishida, Purinergic P2Y6 receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension, Science Signaling, 10.1126/scisignal.aac9187, 9, 411, 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 b-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 vascularsmoothmuscle 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..
4. Akiyuki Nishimura, Maurine E. Linder, Identification of a novel prenyl and palmitoyl modification at the CaaX motif of Cdc42 that regulates RhoGDI binding, Molecular and Cellular Biology, 10.1128/MCB.01398-12, 33, 7, 1417-1429, 2013.04, Membrane localization of Rho GTPases is essential for their biological functions and is dictated in part by a series of posttranslational modifications at a carboxyl-terminal CaaX motif: prenylation at cysteine, proteolysis of the aaX tripeptide, and carboxymethylation. The fidelity and variability of these CaaX processing steps are uncertain. The brain-specific splice variant of Cdc42 (bCdc42) terminates in a CCIF sequence. Here we show that brain Cdc42 undergoes two different types of posttranslational modification: classical CaaX processing or novel tandem prenylation and palmitoylation at the CCaX cysteines. In the dual lipidation pathway, bCdc42 was prenylated, but it bypassed proteolysis and carboxymethylation to undergo modification with palmitate at the second cysteine. The alternative postprenylation processing fates were conserved in the GTPases RalA and RalB and the phosphatase PRL-3, proteins terminating in a CCaX motif. The differentially modified forms of bCdc42 displayed functional differences. Prenylated and palmitoylated brain Cdc42 did not interact with RhoGDI and was enriched in the plasma membrane relative to the classically processed form. The alternative processing of prenylated CCaX motif proteins by palmitoylation or by endoproteolysis and methylation expands the diversity of signaling GTPases and enables another level of regulation through reversible modification with palmitate..
5. Akiyuki Nishimura, Ken Kitano, Jun Takasaki, Masatoshi Taniguchi, Norikazu Mizuno, Kenji Tago, Toshio Hakoshima, Hiroshi Itoh, Structural basis for the specific inhibition of heterotrimeric G q protein by a small molecule, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1003553107, 107, 31, 13666-13671, 2010.08, Heterotrimeric GTP-binding proteins (G proteins) transmit extracellular stimuli perceived by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. Hundreds of GPCRs exist in humans and are the targets of a large percentage of the pharmaceutical drugs used today. Because G proteins are regulated by GPCRs, small molecules that directly modulate G proteins have the potential to become therapeutic agents. However, strategies to develop modulators have been hampered by a lack of structural knowledge of targeting sites for specific modulator binding. Here we present the mechanism of action of the cyclic depsipeptide YM-254890, which is a recently discovered G q-selective inhibitor. YM-254890 specifically inhibits the GDP/GTP exchange reaction of α subunit of Gq protein (Gαq) by inhibiting the GDP release from Gαq. X-ray crystal structure analysis of the Gαqβγ-YM- 254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the Gαq. The binding stabilizes an inactive GDP-bound form through direct interactions with switch I and impairs the linker flexibility. Our studies provide a novel targeting site for the development of small molecules that selectively inhibit each Gα subunit and an insight into the molecular mechanism of G protein activation..
6. Akiyuki Nishimura, Miyuki Okamoto, Yo Sugawara, Norikazu Mizuno, Junji Yamauchi, Hiroshi Itoh, Ric-8A potentiates Gq-mediated signal transduction by acting downstream of G protein-coupled receptor in intact cells, Genes to Cells, 10.1111/j.1365-2443.2006.00959.x, 11, 5, 487-498, 2006.05, RIC-8 was originally found by genetic studies on in vitro as a guanine nucleotide exchange factor for G protein α subunits. However, the physiological role of a mammalian homolog Ric-8A on G protein-coupled receptor signaling in intact cells is largely unknown. We isolated Ric-8A using a yeast two-hybrid system with Gαq and examined the role of Ric-8A on Gq-mediated signaling. The small interfering RNA of Ric-8A diminished the Gq-coupled receptor-mediated ERK activation and intracellular calcium mobilization in 293T cells. Ric-8A was translocated to the cell membrane in response to the Gq-coupled receptor stimulation. The expression of the myristoylation sequence-conjugated Ric-8A mutant was located in the membranes and shown to enhance the Gq-coupled receptor-mediated ERK activation. Moreover, this enhancement on ERK activation and the guanine nucleotide exchange activity of Ric-8A for Gαq were inhibited by Gq selective inhibitor YM-254890. These results suggested that Ric-8A potentiates Gq-mediated signal transduction by acting as a novel-type regulator in intact cells..
Presentations
1. Akiyuki Nishimura, Caroline Sunggip, Takuro Numaga-Tomita and Motohiro Nishida, Developmentally upregulated P2Y6 receptor promotes angiotensin II-induced hypertensive signaling., 3rd CU-NIPS symposium, 2017.01.
2. Akiyuki Nishimura, Caloline Sunggip, Takuro Numaga-Tomita, Motohiro Nishida , Developmentally upregulated P2Y6 receptor promotes angiotensin II-induced hypertensive signaling., International and Interdisciplinary Symposium 2016, 2016.07.
3. Akiyuki Nishimura, Tomoya Ito, Takuro Numaga-Tomita, Motohiro Nishida, Redox-dependent Regulation of H-Ras palmitoylation., 第9回国際NO学会, 2016.05.
Membership in Academic Society
  • Nitric Oxide Society of Japan
  • The Physiological Society of Japan
  • The Pharmaceutical Society of Japan
  • The Japanese Pharmacological Society